Piperazine substituted aryl benzodiazepines and their use as dopamine receptor antagonists for the treatment of psychotic disorders

ABSTRACT

Described herein are antipyschotic compounds of formula (I) wherein, A is an optionally benzo-fused five or six member aromatic ring having zero to three hetero atoms independently selected from N, O, and S; Alk is (C 1-4 ) alkylene optionally substituted with OH, methoxy, ethoxy, or F; Ar is optionally substituted phenyl, naphthyl, monocyclic heteroaromatic, or bicyclic heteroaromatic; R 1  is hydrogen or (C 1-4 ) alkyl optionally substituted with OH, OR 3 , or OCH 2 CH 2 OH, wherein R 3  is (C 1-2 ) alkyl; R 2  is H, (C 1-6 ) alkyl, halogen, fluorinated (C 1-6 ) alkyl, OR 4 , SR 4 , NO 2 , CN, COR 4 , CONR 5 R 6 , SO 2 NR 5 R 6 , NR 5 R 6 , NR 5 COR 4 , NR 5 SO 2 R 4 , or optionally substituted phenyl, wherein R 4  is hydrogen, (C 1-6 ) alkyl, fluorinated (C 1-6 ) alkyl, benzyl, or optionally substituted phenyl, R 5  and R 6  are independently hydrogen, (C 1-6 ) alkyl, or optionally substituted phenyl; Z is one or two substituents independently selected from hydrogen, halogen, (C 1-6 ) alkyl, fluorinated (C 1-6 ) alkyl, OR 7 , SR 7 , NO 2 , CN, COR 7 , CONR 8 R 9 , SO 2 NR 8 R 9 , NR 8 SO 2 R 7 , NR 8 R 9 , or optionally substituted phenyl, wherein R 7  is hydrogen, (C 1-6 ) alkyl, fluorinated alkyl, benzyl, or optionally substituted phenyl, R 8  and R 9  are independently hydrogen, (C 1-6 ) alkyl, or optionally substituted phenyl; and salts, solvates, and crystal forms thereof. Also described are the use of the compounds of formula (a) as antagonists of the dopamine D 2  receptor and as agents for the treatment of psychosis and bipolar disorders, and pharmaceutical formulations of the compounds of formula (I). Also described are compounds useful as intermediates for the synthesis of the compounds of formula (I).

BACKGROUND OF THE INVENTION

Currently there are many drugs available for the treatment of disordersof the central nervous system. Among these drugs is a category known asantipsychotics for treating serious mental conditions such asschizophrenia and schizophreniform illnesses. The drugs availab]e forsuch conditions are often associated with undesirable adverse events,and there is a need for better products that control or eliminate thesymptoms in a safer and more effective way.

Patients suffering from schizophrenia, a condition of unknown etiology,exhibit a group of both positive and negative symptoms. Positivesymptoms include delusions, hallucinations, disordered thoughts, anddisorganized speech, while negative symptoms include flat affect,anhedonia, social withdrawal, emotional detachment, cognitive deficits,and poverty of speech. Not only does schizophrenia cause personalsuffering by the patient, it also severely affects the patient'soccupational and social functions, so that often the patient must beinstitutionalized, which results in a high cost to society.

A leading hypothesis suggests that the positive symptoms ofschizophrenia can be effectively treated by compounds that act asantagonists at certain dopamine receptors. Currently, five principaldopamine receptors (D₁-D₅) that have been identified. Antipsychoticefficacy has been most closely associated with blockade of the D2 classof dopamine receptors. The typical antipsychotic agents (eg.haloperidol) are effective in controlling the positive symptoms ofschizophrenia but do not adequately treat the negative symptoms and alsoinduce significant adverse events, principally extrapyramidal sideeffects, hyperprolactinemia, and tardive dyskinesia.

One approach to developing better antipsychotic agents, involves theidentification of compounds that combine D2 receptor blockade withactions at other receptors. One such agent is clozapine.

Clozapine was the first drug identified as an “atypical” antipsychotic,i.e., a drug effective in treating both the positive and negativesymptoms of schizophrenia. Additionally, it did not cause EPS and theother adverse events seen with classical, “typical” antipsychotics.Although clozapine is an effective drug, its utility in treatingschizophrenia has been limited because of the clinical observation that1-2% of treated patients developed a potentially fatal blood disorder.More recently, olanzapine has been widely accepted as an atypicalantipsychotic with relatively few adverse events. Atypicalantipsychotics like clozapine and olanzapine are D2 receptor antagonistsand also interact with receptor subtypes for several neurotransmitters,including doparnine, serotonin, norepinephrine, histamine, andacetylcholine. It is believed that some of these additional receptoractivities are responsible for the improved efficacy of the atypicalantipsychotics and that the adverse events of these agents may bemediated by interactions with others. The success of the atypicalantipsychotic drugs has inspired research to produce even more effectivedrugs for the treatment of schizophrenia that would have negligibleinstances of adverse events.

The present invention provides antipsychotic compounds and methods ofusing those compounds to treat psychotic disorders, in particular,schizophrenia and mood disorders, such as bipolar disorders. Thesecompounds offer certain improvements and advantages over theantipsychotics currently in clinical use.

BRIEF SUMMARY OF THE INVENTION

One aspect of the present invention provides compounds of formula (I):

wherein,

-   -   A is an optionally benzo-fused five or six member aromatic ring        having zero to three hetero atoms independently selected from N,        O, and S;    -   Alk is (C₁₋₄) alkylene optionally substituted with OH, methoxy,        ethoxy, or F;    -   Ar is optionally substituted phenyl, naphthyl, monocyclic        heteroaromatic, or bicyclic heteroaromatic;    -   R¹ is hydrogen or (C₁₋₄) alkyl optionally substituted with OH,        OR³, or OCH₂CH₂OH,        -   wherein R³ is (C₁₋₂) alkyl;    -   R² is H, (C₁₋₆) alkyl, halogen, fluorinated (C₁₋₆) alkyl, OR⁴,        SR⁴, NO₂, CN, COR⁴, CONR⁵R⁶, SO₂NR⁵R⁶, NR⁵R⁶, NR⁵COR⁴, NR⁵SO₂R⁴,        or optionally substituted phenyl,        -   wherein        -   R⁴ is hydrogen, (C₁₋₆) alkyl, fluorinated (C₁₋₆) alkyl,            benzyl, or optionally substituted phenyl,        -   R⁵ and R⁶ are independently hydrogen, (C₁₋₆) alkyl, or            optionally substituted phenyl;    -   Z is one or two substituents independently selected from        hydrogen, halogen, (C₁₋₆) alkyl, fluorinated (C₁₋₆) alkyl, OR⁷,        SR⁷, NO₂, CN, COR⁷, CONR⁸R⁹, SO₂NR⁸R⁹, NR⁸SO₂R⁷, NR⁸R⁹, or        optionally substituted phenyl,        -   wherein        -   R⁷ is hydrogen, (C₁₋₆) alkyl, fluorinated (C₁₋₆) alkyl,            benzyl, or optionally substituted phenyl,        -   R⁸ and R⁹ are independently hydrogen, (C₁₋₆) alkyl, or            optionally substituted phenyl;    -   and salts, solvates, and crystal forms thereof.

Another aspect of the present invention provides compounds of formula(Ia):

wherein,

-   -   Alk is (C₁₋₄) alkylene optionally substituted with OH;    -   Ar is optionally substituted phenyl, naphthyl, monocyclic        heteroaromatic, or bicyclic heteroaromatic;    -   R¹ is hydrogen or (C₁₋₄) alkyl;    -   R² is H, (C₁₋₆) alkyl, fluorinated (C₁₋₆) alkyl,    -   Z is one or two substituents independently selected from        hydrogen, or halogen, and salts, solvates, and crystal forms        thereof.

Another aspect of the present invention provides compounds of formula(Ib):

wherein,

-   -   Alk is (C₁₋₄) alkylene;    -   Ar is optionally substituted phenyl,    -   R¹ is hydrogen or (C₁₋₄) alkyl;    -   R² is H, or (C₁₋₆) alkyl;    -   Z is one or two substituents independently selected from        hydrogen, or halogen; and salts, solvates, and crystal forms        thereof.

Another aspect of the present invention provides compounds of formula(Ic):

wherein,

-   -   Alk is (C₁₋₄) alkylene optionally substituted with OH;    -   Ar is optionally substituted phenyl;    -   R¹ is hydrogen or (C₁₋₄) alkyl;    -   R² is H, (C₁₋₆) alkyl, halogen, or fluorinated (C₁₋₆) alkyl;    -   Z is one or two substituents independently selected from        hydrogen, or halogen; and salts, solvates, and crystal forms        thereof.

Another aspect of the present invention provides compounds of formula(Id):

wherein,

-   -   Alk is (C₁₋₄) allylene;    -   Ar is optionally substituted phenyl;    -   R¹ is hydrogen or (C₁₋₄) alkyl;    -   R² is H, or (C₁₋₆) alkyl;    -   Z is one or two substituents independently selected from        hydrogen, or halogen; and salts, solvates, and crystal forms        thereof

Another aspect of the present invention provides compounds of formula(Ie):

wherein,

-   -   Alk is (C₁₋₄) alkylene;    -   Ar is optionally substituted phenyl;    -   R¹ is hydrogen or (C₁₋₄) alkyl    -   R² is H, (C₁₋₆) alkyl, halogen, fluorinated (C₁₋₆) alkyl, or CN;    -   Z is one or two substituents independently selected from        hydrogen, or halogen; and salts, solvates, and crystal forms        thereof.

Another aspect of the present invention is the novel intermediatecompounds taught herein in the synthesis of compounds of formula (I).

Another aspect of the present invention is a novel process tointermediate compounds taught herein in the synthesis of compounds offormula (I).

Another aspect of the present invention is the use the compounds offormula (I) as dopamine D₂ antagonists, and their use in treatingpatients suffering from a psychotic condition or mood disorder,including for example schizophrenia and bipolar disorders.

Another aspect is the pharmaceutical formulations which comprises, inassociation with a pharmaceutically acceptable carrier, diluent orexcipient, compound of formula (I).

DETAILED DESCRIPTION OF THE INVENTION

Terms and symbols used herein have meanings consistent with usage incontemporary chemical literature unless otherwise noted. For example,the term “(C₁₋₆) alkyl” includes saturated and unsaturated alkyl groupsthat may be branched straight chain or cyclic such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl,2-pentyl, 3-pentyl, neopentyl, n-hexyl, —CH₂CH₂═CH₂, —CH₂CH═C(CH₃)₂,—CH₂C(═CH₂)CH₃, cyclopropyl, cyclopropylmethyl, cyclopentyl, cyclohexyl,and the like. The term “(C₁₋₄) alkylene” refers to —CH₂—, —CH₂CH₂—,—CH₂CH₂CH₂—, and —CH₂CH₂CH₂CH₂—. The term “halogen” includes fluoro,chloro, bromo and iodo. The term “fluorinated (C₁₋₆) alkyl” refers to a(C₁₋₆) alkyl group which is substituted with one or more fluorines, suchas, fluoromethyl, difluoromethyl, trifluoromethyl, 2-fluoroethyl,2,2,2-trifluoroethyl, 1,1,2,2,2-pentafluoroethyl, 3-fluoropropyl,3,3,3-trifluoropropyl, 1,1,1,3,3,3-hexafluoroprop-2-yl, and6-fluorohexyl.

The term “optionally substituted phenyl” refers to a phenyl group whichmay be substituted with one to three substituents selected fromhydrogen, halogen, (C₁₋₆) alkyl, fluorinated (C₁₋₆) alkyl, OH, (C₁₋₆)alkoxy, (C₁₋₆) fluorinated alkoxy, (C₁₋₆) thioalkyl, (C₁₋₆) acyl, (C₁-C₄alkyl)sulfonyl, OCF₃, NO₂, CN, carboxamido which may be substituted onthe nitrogen by one or two (C₁₋₄) alkyl groups, and NH₂ in which one ofthe hydrogens may be replaced by a (C₁₋₄) alkyl group and the otherhydrogen may be replaced by either a (C₁₋₄) alkyl group, a (C₁₋₆) acylgroup, or a (C₁-C₄ alkyl)sulfonyl group. The term “(C₁₋₆) alkoxy”includes such groups as methoxy, ethoxy, isopropoxy, sec-butoxy,tert-butoxy, 2-pentoxy, 3-hexyloxy, and the like. The term “(C₁₋₆)alkylthio” includes such groups as methylthio, ethylthio, isopropylthio,sec-butylthio, tert-butylthio, 1-hexylthio, and the like. The term“(C₁₋₆) acyl” includes, for example, formyl, acetyl, propanoyl,butanoyl, 2-methylpropanoyl, hexanoyl, and the like. The term “(C₁-C₄alkyl)sulfonyl” includes methanesulfonyl, ethanesulfonyl,propanesulfonyl, isopropanesulfonyl, 1-butanesulfonyl and the like.

The term “monocyclic heteroaromatic” refers to a five or six memberedaromatic ring containing one to three heteroatoms selected from N, O,and S. Recognize that if one of the heteroatoms is O or S, theheteroaromatic ring must be a five membered ring and that any otherheteroatoms contained therein must be N. Examples of such monocyclicheteroaromatic systems include furan, thiophene, pyridine, pyrimidine,thiazole, 1,2,3-triazole, and the like.

The term “bicyclic heteroaromatic” refers to a bicyclic aromatic systemcontaining one to three heteroatoms selected from N, O, and S. Examplesinclude indole, benzofuran, benzothiophene, quinoline, isoquinoline,indazole, benzothiazole, and the like.

The term “optionally substituted phenyl, naphthyl, monocyclicheteroaromatic, or bicyclic heteroaromatic” refers to phenyl, naphthyl,monocyclic heteroaromatic, or bicyclic heteroaromatic which may besubstituted with one to three substituents selected from hydrogen,halogen, (C₁₋₆) alkyl, fluorinated (C₁₋₆) alkyl, OH, (C₁₋₆) alkoxy,(C₁₋₆) fluorinated alkoxy, (C₁₋₆) thioalkyl, (C₁₋₆) acyl, (C₁-C₄alkyl)sulfonyl, OCF₃, NO₂, CN, carboxamido which may be substituted onthe nitrogen by one or two (C₁₋₄) alkyl groups, and NH₂ in which one ofthe hydrogens may be replaced by a (C₁₋₄) alkyl group and the otherhydrogen may be replaced by either a (C₁₋₄) alkyl group, a (C₁₋₆) acylgroup, or a (C₁-C₄ alkyl)sulfonyl group.

In the case of optionally benzo-fused five or six member aromatic ringhaving zero to three hetero atoms independently selected from N, O, andS, the two atoms of the aromatic ring which are fused to the adjoiningseven member ring are constrained to both be carbon. If the aromaticring contains two additional adjacent carbon atoms, a benzene ring maybe fused to the aromatic ring at those two adjacent carbon atoms.Examples of optionally benzo-fused five or six member aromatic ringshaving zero to three hetero atoms independently selected from N, S, andO include benzene, pyridine, furan, pyrrole, thiophene, thiazole,oxazole, pyrazole, imidazole, 1,2,3-triazole, naphthylene, quinoline,isoquinoline, indole, benzofuran, benzothiophene, and the like.

The compounds of the present invention may, depending upon theirstructure and manner of synthesis and isolation, exist as apharmaceutically acceptable solvate. These solvates include water,methanol, and ethanol. Solvated forms of the compounds ofthe presentinvention represent a further embodiment of the present invention.

The compounds of formula (I) can exist in optically isomeric forms, ie.,stereoisomeric forms. That is, these compounds have a least one chiral,ie., asymmetric, center at the carbon atom of the piperazine ring towhich “Ak” is attached. Such asymmetry gives rise to at least one pairof enantiomers. An equal mixture of enantiomers is known as a “racemic”mixture or a “racemate.” The representation of formula (I) is intendedto represent each of those stereoisomers and mixtures thereof.

The terms “R” and “S” are used herein as commonly used in organicchemistry to denote specific configuration of a chiral center. The term“R” (rectus) refers to that configuration of a chiral center with aclockwise relationship of group priorities (highest to second lowest)when viewed along the bond toward the lowest priority group. The term“S” (sinister) refers to that configuration of a chiral center with acounterclockwise relationship of group priorities (highest to secondlowest) when viewed along the bond toward the lowest priority group. Thepriority of groups is based upon their atomic number (in order ofdecreasing atomic number). Some of the compounds of formula (I) may havetwo or more chiral centers.

Some of the compounds of the present invention may also be isomeric withrespect to one or more double bonds, which introduces geometric, i.e.,cis and trans, isomers. A discussion of optical and geometric isomerscan be found in standard organic chemistry text books such as March'sAdvanced Organic Chemistry, 5^(th) Ed., Chapter 4, Wiley-Interscience,John Wiley & Sons, Inc., New York (2001). Herein, when a compound of thepresent invention is named, or its structure presented, without anindication of asymmetric form, all of the possible asymmetric forms areintended This invention is not limited to any particular isomer butincludes all possible individual isomers and racemates.

Preferred among the compounds of formula (I) are those wherein:

-   -   a) The aromatic ring A is selected from the group consisting of:

Preferred among the compounds of formula (I) are those wherein:

-   -   b) Alk is —CH₂—, —CH₂CH₂—, or —CH₂CH₂CH₂—;

Another preferred embodiment among the compounds of formula (I) arethose wherein:

-   -   c) Ar is optionally substituted phenyl furan, or thiophene;

Another preferred embodiment among the compounds of formula (I) arethose wherein:

-   -   d) R¹ is hydrogen, methyl, or —CH₂CH₂—O—CH₂CH₂—OH;

Another preferred embodiment among the compounds of formula (I) arethose wherein:

-   -   e) Z is hydrogen or halogen;

Another preferred embodiment among the compounds of formula (I) arethose wherein:

-   -   f) The stereo configuration is “S” about the carbon of the        piperazine group bound to Alk.

Another preferred embodiment among the compounds of formula (I) arethose wherein:

-   -   g) R² is hydrogen, (C₁₋₆) alkyl, fluorinated (C₁₋₆) alkyl, or        halogen.

It is an aspect of this invention that any combination of thesepreferred embodiments are contemplated.

The compounds of formula (If) listed in Table 1 are of particularinterest:

The stereo configuration is “S” about the carbon of the piperazine groupbound to Alk unless otherwise indicated. TABLE 1 Ex. No. E₁ E₂ E₃ Alk ArR¹ R² Z  59 CH C S CH₂CH₂Ph H CH₃ H  61 CH C S CH₂Ph H CH₃ H  62 CH C SCH₂(4-OCH₂CH═C(CH₃)₂)Ph H CH₃ H  63 CH C S CH₂(3,4-OCH₂O—)Ph H CH₃ H  64CH C S CH₂(3,4-diOCH₃)Ph H CH₃ H  65 CH C S CH₂(4-iPr)Ph H CH₃ H  66 CHC S CH₂(4-PhO)Ph H CH₃ H  67 CH C S CH₂(napthalen-2-yl) H CH₃ H  68 CH CS CH₂(napthalen-1-yl) H CH₃ H  69 CH C S CH₂(4-CH₃)Ph H CH₃ H  70 CH C SCH₂(3-CH₃)Ph H CH₃ H  71 CH C S CH₂(2-F)Ph H CH₃ H  72 CH C S CH₂(3-F)PhH CH₃ H  73 CH C S CH₂(4-F)Ph H CH₃ H  74 CH C S CH₂(2-CF₃)Ph H CH₃ H 75 CH C S CH₂(2-OCH₃)Ph H CH₃ H  76 CH C S CH₂(3-OCH₃)Ph H CH₃ H  77 CHC S CH₂(4-OCH₃)Ph H CH₃ H  78 CH C S CH₂(3,4-diCl)Ph H CH₃ H  79 CH C SCH₂(indol-3-yl) H CH₃ H  80 CH C S CH₂(thiophen-2-yl) H CH₃ H  81 CH C SCH₂(benzo(b)thiophen-3-yl) H CH₃ H  82 CH C S CH₂(3-O-i-Pr)Ph H CH₃ H 83 CH C S (R)CH₂Ph H CH₃ H  84 CH C S CH₂(2,4-DiOCH₃)Ph H CH₃ H  85 CHC S CH₂(4-Cl)Ph H CH₃ H  86 CH C S CH₂(2-Cl)Ph H CH₃ H  87 CH C SCH₂(3-Cl)Ph H CH₃ H  88 CH C S CH₂(3,5-DiF)Ph H CH₃ H  89 CH C SCH₂(3-CF₃)Ph H CH₃ H  90 CH C S CH₂CH₂Ph CH₃ CH₃ H  92 CH C S CH₂Ph CH₃CH₃ H  93 CH C S CH₂(4-O—CH₂CH═CH₂)Ph CH₃ CH₃ H  94 CH C SCH₂(pyridin-2-yl) CH₃ CH₃ H  95 CH C S (R)CH₂Ph CH₃ CH₃ H 100 CH C SCH₂(napthalen-2-yl) CH₃ CH₃ H 101 CH C S CH₂(napthalen-1-yl) CH₃ CH₃ H102 CH C S CH₂(4-CH₃)Ph CH₃ CH₃ H 103 CH C S CH₂(3-CH₃)Ph CH₃ CH₃ H 104CH C S CH₂(2-F)Ph CH₃ CH₃ H 105 CH C S CH₂(3-F)Ph CH₃ CH₃ H 106 CH C SCH₂(4-F)Ph CH₃ CH₃ H 107 CH C S CH₂(3-CF₃)Ph CH₃ CH₃ H 108 CH C SCH₂(2-CF₃)Ph CH₃ CH₃ H 109 CH C S CH₂(2-OCH₃)Ph CH₃ CH₃ H 110 CH C SCH₂(3-OCH₃)Ph CH₃ CH₃ H 111 CH C S CH₂(4-OCH₃)Ph CH₃ CH₃ H 112 CH C SCH₂(3,4-diCl)Ph CH₃ CH₃ H 113 CH C S CH₂(indol-3-yl) CH₃ CH₃ H 114 CH CS CH₂(thiophen-2-yl) CH₃ CH₃ H 115 CH C S CH₂(benzo(b)thiophen-3-yl) CH₃CH₃ H 118 CH C S CH₂(2-Cl)Ph CH₃ CH₃ H 119 CH C S CH₂(3-Cl)Ph CH₃ CH₃ H120 CH C S CH₂(4-Cl—Ph) CH₃ CH₃ H 121 CH C S CH₂(4-OPh)Ph CH₃ CH₃ H 122CH C S CH₂(3-OPh)Ph CH₃ CH₃ H 123 CH C S CH₂(3-O-iPr)Ph CH₃ CH₃ H 124 CHC S CH₂(2,4-di OCH₃)Ph CH₃ CH₃ H 132 CH C S CH₂CH₂(2-pyridin-2-yl) H CH₃H 133 CH C S CH₂CH₂(2-pyridin-4-yl) H CH₃ H 176 CH C S CH₂CH₂(4-F)Ph HCH₃ H 177 CH C S CH₂CH₂(3-F)Ph H CH₃ H 178 CH C S CH₂CH₂(2-F)Ph H CH₃ H179 CH C S CH₂CH₂(4-OCH₃)Ph H CH₃ H 180 CH C S CH₂CH₂(3-OCH₃)Ph H CH₃ H181 CH C S CH₂CH₂(2-OCH₃)Ph H CH₃ H 182 CH C S CH₂CH₂(4-F)Ph CH₃ CH₃ H183 CH C S CH₂CH₂(3-F)Ph CH₃ CH₃ H 184 CH C S CH₂CH₂(2-F)Ph CH₃ CH₃ H185 CH C S CH₂CH₂(4-OCH₃)Ph CH₃ CH₃ H 186 CH C S CH₂CH₂(3-OCH₃)Ph CH₃CH₃ H 187 CH C S CH₂CH₂(2-OCH₃)Ph CH₃ CH₃ H 188 CH C SCH₂CH₂(2-pyridin-4-yl) CH₃ CH₃ H 189 CH C S CH₂CH₂(2-pyridin-3-yl) H CH₃H 190 CH C S CH₂CH₂(2-pyridin-3-yl) CH₃ CH₃ H 191 CH C SCH₂CH₂(2-pyridin-2-yl) CH₃ CH₃ H 194 CH C S (CH₂)₄Ph H CH₃ H 195 CH C S(CH₂)₄Ph CH₃ CH₃ H 201 CH C S (CH₂)₃Ph H CH₃ H 202 CH C S (CH₂)₃Ph CH₃CH₃ H 209 CH C S CH₂(4-Br)Ph H CH₃ H 210 CH C S CH₂(4-I)Ph H CH₃ H 211CH C S CH₂(4-O—CH₂CH═CH₂)Ph H CH₃ H 212 CH C S CH₂(thiaphen-3-yl) H CH₃H 213 CH C S CH₂(4-O-isoPropyl)Ph H CH₃ H 218 CH C S CH₂(4-Br)Ph CH₃ CH₃H 219 CH C S CH₂(thiophen-3-yl) CH₃ CH₃ H 220 CH C S CH₂(4-I)Ph CH₃ CH₃H 221 CH C S CH₂(4-O-isoPropyl)Ph CH₃ CH₃ H 236 CH C S CH₂(3,5-DiCH₃)PhH CH₃ H 237 CH C S CH₂(4-O—CH₂C(═CH₂)CH₃)Ph H CH₃ H 238 CH C SCH₂(2-OEt)Ph H CH₃ H 239 CH C S CH₂(2-O—iPr)Ph H CH₃ H 240 CH C SCH₂(pyridin-2-yl) H CH₃ H 240a CH C S CH₂(3-OPh)Ph H CH₃ H 241 CH C SCH₂(4-O—CH₂CH═C(CH₃)₂)Ph CH₃ CH₃ H 242 CH C S CH₂(3,4-OCH₂O—)Ph CH₃ CH₃H 243 CH C S CH₂(3,4-Di(OCH₃))Ph CH₃ CH₃ H 244 CH C SCH₂(4-O—CH₂C(═CH₂)CH₃)Ph CH₃ CH₃ H 245 CH C S CH₂(4-isoPropyl)Ph CH₃ CH₃H 246 CH C S CH₂(3,5-Di(CH₃))Ph CH₃ CH₃ H 247 CH C S CH₂(2-OCH₂CH₃)PhCH₃ CH₃ H 248 CH C S CH₂(4-Ph)Ph CH₃ CH₃ H 249 CH C SCH₂(2-O-isoPropyl)Ph CH₃ CH₃ H 387 CH C S CH₂CH₂(3-Cl)Ph H CH₃ H 388 CHC S CH₂CH₂(4-Cl)Ph H CH₃ H 389 CH C S CH₂CH₂(2-Cl)Ph H CH₃ H 390 CH C SCH₂CH₂(4-Cl)Ph CH₃ CH₃ H 391 CH C S CH₂CH₂(3-Cl)Ph CH₃ CH₃ H 392 CH C SCH₂CH₂(2-Cl)Ph CH₃ CH₃ H 393 CH C S CH₂CH₂(4-CF₃)Ph H CH₃ H 394 CH C SCH₂CH₂(2-CF₃)Ph H CH₃ H 395 CH C S CH₂CH₂(3-CF₃)Ph H CH₃ H 396 CH C SCH₂CH₂(4-CF₃)Ph CH₃ CH₃ H 397 CH C S CH₂CH₂(2-CF₃)Ph CH₃ CH₃ H 398 CH CS CH₂CH₂(3-CF₃)Ph CH₃ CH₃ H 399 CH C S CH₂CH₂(2,4-diF)Ph H CH₃ H 400 CHC S CH₂CH₂(2,4-diF)Ph CH₃ CH₃ H 401 CH C S CH₂CH₂(3-F)Ph H CH₃ 6F 402 CHC S CH₂CH₂(4-OCH₃)Ph H CH₃ 6F 403 CH C S CH₂CH₂(3-F)Ph H CH₃ 7F 404 CH CS CH₂CH₂(4-OCH₃)Ph H CH₃ 7F 405 CH C S CH₂CH₂(3-F)Ph CH₃ CH₃ 6F 406 CH CS CH₂CH₂(4-OCH₃)Ph CH₃ CH₃ 6F 407 CH C S CH₂CH₂(3-F)Ph CH₃ CH₃ 7F 408 CHC S CH₂CH₂(4-OCH₃)Ph CH₃ CH₃ 7F 411 CH C S CH₂CH₂(3-F)Ph H CH₂CH₃ 7F 412CH C S CH₂CH₂(3-F)Ph CH₃ CH₂CH₃ 7F 413 CH C S CH₂CH₂(4-OCH₃)Ph H CH₂CH₃7F 414 CH C S CH₂CH₂(4-OCH₃)Ph CH₃ CH₂CH₃ 7F 423 CH C SCH₂CH₂(2-napthalen-1-yl) H CH₃ H 425 CH C S CH₂CH₂(2-napthalen-1-yl) CH₃CH₃ H 428 CH C S CH₂CH₂(2-napthalen-2-yl) H CH₃ H 429 CH C SCH₂CH₂(2-napthalen-2-yl) CH₃ CH₃ H 434 CH C S CH₂CH₂(2-furan-3-yl) H CH₃H 435 CH C S CH₂CH₂(2-furan-3-yl) CH₃ CH₃ H 439 CH C SCH₂CH₂(2-thiophene-3-yl) H CH₃ H 440 CH C S CH₂CH₂(2-thiophene-3-yl) CH₃CH₃ H 441 CH C S CH₂Ph H CH(CH₃)₂ H 442 CH C S CH₂CH₂Ph H CH(CH₃)₂ H 443CH C S CH₂(2-OCH₃)Ph H CH(CH₃)₂ H 444 CH C S CH₂CH₂Ph CH₃ CH(CH₃)₂ H444a CH C S CH₂Ph CH₃ CH(CH₃)₂ H 444b CH C S CH₂(2-OCH₃)Ph CH₃ CH(CH₃)₂H 445 CH C S CH₂CH₂Ph H C(CH₃)₃ H 446 CH C S CH₂CH₂Ph CH₃ C(CH₃)₃ H 460N C S CH₂CH₂Ph H CH₃ H 461 N C S CH₂CH₂Ph CH₃ CH₃ H 462 N C S CH₂Ph HCH₃ H 463 N C S CH₂(2-OCH₃)Ph H CH₃ H 464 N C S CH₂CH₂(4-OCH₃)Ph H CH₃ H465 N C S CH₂CH₂(4-OCH₃)Ph CH₃ CH₃ H 466 N C S CH₂CH₂(4-F)Ph H CH₃ H 467N C S CH₂CH₂(3-F)Ph H CH₃ H 468 N C S CH₂CH₂Ph H CH(CH₃)₂ H 469 N C SCH₂CH₂(4-OCH₃)Ph H CH(CH₃)₂ H 470 N C S CH₂Ph H CH(CH₃)₂ H 471 N C SCH₂CH₂(3-F)Ph H CH(CH₃)₂ H 472 N C S CH₂CH₂(4-F)Ph H CH(CH₃)₂ H 473 N CS CH₂Ph CH₃ CH₃ H 474 N C S CH₂(2-OCH₃)Ph CH₃ CH₃ H 475 N C S CH₂CH₂PhCH₃ CH(CH₃)₂ H 476 N C S CH₂CH₂(4-OCH₃)Ph CH₃ CH(CH₃)₂ H 477 N C S CH₂PhCH₃ CH(CH₃)₂ H 478 N C S CH₂CH₂(4-F)Ph CH₃ CH₃ H 479 N C S CH₂CH₂(3-F)PhCH₃ CH₃ H 480 N C S CH₂CH₂(3-F)Ph CH₃ CH(CH₃)₂ H 481 N C S CH₂CH₂(4-F)PhCH₃ CH(CH₃)₂ H 484 N C S CH₂CH₂Ph H CH₂CH₂ H CH₂CH₃ 486 N C S CH₂CH₂PhCH₃ CH₂CH₂ H CH₂CH₃ 491 N C S CH₂CH₂Ph H cyclopentyl H 492 N C SCH₂CH₂Ph CH₃ cyclopentyl H 493 N C S CH₂Ph H cyclopentyl H 494 N C SCH₂Ph CH₃ cyclopentyl H 495 N C S CH₂CH₂(3-OCH₃)Ph H cyclopentyl H 496 NC S CH₂CH₂(3-OCH₃)Ph CH₃ cyclopentyl H 497 N C S CH₂CH₂(4-OCH₃)Ph Hcyclopentyl H 498 N C S CH₂CH₂(4-OCH₃)Ph CH₃ cyclopentyl H 501 N C SCH₂CH₂(4-OCH₃)Ph H CH₂CH₃ H 502 N C S CH₂CH₂(4-F)Ph H CH₂CH₃ H 503 N C SCH₂CH₂(3-F)Ph H CH₂CH₃ H 504 N C S CH₂CH₂(3-OCH₃)Ph H CH₂CH₃ H 506 N C SCH₂CH₂(4-OCH₃)Ph CH₃ CH₂CH₃ H 507 N C S CH₂CH₂(4-F)Ph CH₃ CH₂CH₃ H 508 NC S CH₂CH₂(3-F)Ph CH₃ CH₂CH₃ H 509 N C S CH₂CH₂(3-OCH₃)Ph CH₃ CH₂CH₃ H512 N C S CH₂CH₂(3-F)Ph H CF₃ H 514 N C S CH₂CH₂(4-F)Ph H CF₃ H 516 N CS CH₂CH₂(3-OCH₃)Ph H CF₃ H 518 N C S CH₂CH₂(4-OCH₃)Ph H CF₃ H 520 N C SCH₂CH₂(3-OCH₃)Ph CH₃ CF₃ H 522 N C S CH₂CH₂(3-F)Ph CH₃ CF₃ H 524 N C SCH₂CH₂(4-OCH₃)Ph CH₃ CF₃ H 526 N C S CH₂CH₂(4-F)Ph CH₃ CF₃ H 533 C C SCH₂CH₂Ph H benzofused 9F 534 C C S CH₂CH₂Ph CH₃ benzofused 9F 535 C C SCH₂CH₂(4-OCH₃)Ph H benzofused 9F 537 C C S CH₂CH₂(3-OCH₃)Ph H benzofused9F 539 C C S CH₂CH₂(3-F)Ph H benzofused 9F 541 C C S CH₂CH₂(4-F)Ph Hbenzofused 9F 543 C C S CH₂CH₂(4-OCH₃)Ph CH₃ benzofused 9F 545 C C SCH₂CH₂(3-OCH₃)Ph CH₃ benzofused 9F 547 C C S CH₂CH₂(3-F)Ph CH₃benzofused 9F 549 C C S CH₂CH₂(4-F)Ph CH₃ benzofused 9F 568 CH C═CH CHCH₂CH₂(4-F)Ph H 2-CH₃ 8F 569 CH C═CH CH CH₂CH₂(4-F)Ph CH₃ 2-CH₃ 8F 570CH C═CH CH CH₂CH₂(4-F)Ph H 2- 8F CH(CH₃)₂ 571 CH C═CH CH CH₂CH₂(4-F)PhCH₃ 2- 8F CH(CH₃)₂ 572 CH C═CH CH CH₂CH₂(3-F)Ph H 2- H CH(CH₃)₂ 573 CHC═CH CH CH₂CH₂(3-F)Ph CH₃ 2- H CH(CH₃)₂ 575 CH CH═C CH CH₂CH₂Ph H 3-CH₃H 576 CH CH═C CH CH₂CH₂Ph CH₃ 3-CH₃ H 577 CH CH═C CH CH₂CH₂(3-F)Ph H3-CH₃ H 578 CH CH═C CH CH₂CH₂(3-F)Ph CH₃ 3-CH₃ H 580 CH C═CH CH CH₂CH₂PhH 2-CH₃ H 581 CH C═CH CH CH₂CH₂Ph CH₃ 2-CH₃ H 585 CH CH═C CH CH₂Ph H 3-H8Cl 586 CH CH═C CH CH₂CH₂Ph H 3-H 8Cl 587 CH CH═C CH CH₂CH₂Ph CH₃ 3-H8Cl 588 CH CH═C CH CH₂Ph CH₃ 3-H 8Cl 594 N N NH CH₂CH₂Ph H CH(CH₃)₂ H595 N N NH CH₂CH₂Ph CH₃ CH(CH₃)₂ H 598 CH C S (S,R)CH₂CH(OH)Ph H CH₃ H599 CH C S (S,S)CH₂CH(OH)Ph H CH₃ H 600 CH C S (S,S)CH₂CH(OH)Ph CH₃ CH₃H 601 N C S (S,R)CH₂CH(OH)Ph H CH(CH₃)₂ H 602 N C S (S,S)CH₂CH(OH)Ph HCH(CH₃)₂ H 603 N C S (S,S)CH₂CH(OH)Ph CH₃ CH(CH₃)₂ H 609 CH C═CH CHCH₂CH₂(4-OCH₃)Ph H 2-CF₃ 8F 610 CH C═CH CH CH₂CH₂(4-OCH₃)Ph CH₃ 2-CF₃ 8F611 CH C═CH CH CH₂CH₂(4-F)Ph H 2-CF₃ 8F 612 CH C═CH CH CH₂CH₂(4-F)Ph CH₃2-CF₃ 8FCompound number corresponds to example number in the Examples section.

The compounds of formula (Ib) listed in Table 2 are of particularinterest:

The stereo configuration is “S” about the carbon of the piperazine groupbound to Alk unless otherwise indicated. TABLE 2 (Ib)

Ex No.: Alk-Ar R¹ R² Z 533 CH₂CH₂Ph H H 9F 534 CH₂CH₂Ph CH₃ H 9F 535CH₂CH₂(4-OCH₃)Ph H H 9F 537 CH₂CH₂(3-OCH₃)Ph H H 9F 539 CH₂CH₂(3-F)Ph HH 9F 541 CH₂CH₂(4-F)Ph H H 9F 543 CH₂CH₂(4-OCH₃)Ph CH₃ H 9F 545CH₂CH₂(3-OCH₃)Ph CH₃ H 9F 547 CH₂CH₂(3-F)Ph CH₃ H 9F 549 CH₂CH₂(4-F)PhCH₃ H 9FCompound number corresponds to example number in the Examples section.

Since the compounds of this invention are basic in nature, they reactwith any of a number of inorganic and organic acids to form acidaddition salts. For the therapeutic utility taught herein, the salt ofthe claimed compounds must be pharmaceutically acceptable. Acidscommonly employed to form pharmaceutically acceptable salts areinorganic acids such as hydrochloric acid, hydrobromic acid, hydroiodicacid, sulfuric acid, phosphoric acid, and organic acids, such asp-toluenesulfonic acid, methanesulfonic acid, oxalic acid,p-bromo-phenylsulfonic acid, carbonic acid, succinic acid, citric acid,benzoic acid, acetic acid, lactic acid, maleic acid, tartaric acid, andthe like. For further details on pharmaceutically acceptable salts, seeJournal of Pharmaceutical Science, 66,1 (1977). Salts that are notpharmaceutically acceptable may be used as intermediates to prepareother compounds of formula (I) or a pharmaceutically acceptable salt ofcompounds of formula (I) and are within the scope of the presentinvention. Particular pharmaceutically acceptable salts ate those formedwith hydrochloric acid, sulfuric acid, or phosphoric acid.

The intermediates and final products described herein may be isolatedand purified by the conventional techniques known to artisans of organicchemistry. For example, the well-known techniques of chromatography,recrystallization, distillation, and sublimation may be used singularlyand sequentially.

General Synthetic Methods

Compounds of formula (I) of this invention can be prepared by severalmethods generally known in the art of organic chemistry. Startingmaterials, the preparation of which are not described, are commerciallyavailable or can be readily prepared by known techniques fromcommercially available starting materials.

As shown in Scheme 1, compounds of formula (I) may be convenientlyprepared from compounds of formula (IIa), by removal of the protectinggroup “ProG” from the amine nitrogen of the seven-member ring of thetricyclic ring system. The methods for introducing and removing theseprotecting groups are known in the art. See T. W. Green, ProtectiveGroups in Organic Synthesis, John Wiley and Sons, Inc., (1981). Examplesof such ProG groups include benzyl, acetyl, t-butoxycarbonyl,methanesulfonyl, and the like.

As used herein, “Pg” represents either hydrogen or an amine protectinggroup ProG. For those examples in which Pg is an amine protecting group,the penultimate intermediate can be converted to the compound of formula(I) by removal of the protecting group. In the following text, for thoseintermediates containing a group Pg in which Pg is an amine protectinggroup, the protecting group may be removed to give the unprotectedamine. Similarly, for those intermediates in which Pg is hydrogen, anamine protecting group may be incorporated into the intermediate.

Compounds of formula (IIb) in which R¹ is hydrogen can be converted tocompounds of formula (IIc) in which R¹ is (C₁₋₄) alkyl optionallysubstituted with hydroxy, methoxy, ethoxy, or OCH₂CH₂OH. Thistransformation can be accomplished, as shown in Scheme Ia, by treatmentof formula (IIb) with an alkylating agent. Alkylating agents includealkyl halides and alkyl sulfonate esters. Examples include methyliodide, 1-bromobutane, 2-propyl methanesulfonate, and bromoethylmethylether. This reaction is usually performed in the presence of a base andsolvent. The base can be either an organic base such as pyridine ordiisopropylethylamine or an inorganic base such as potassium carbonate.Solvents include methanol, ethanol, THF, and DMF. This transformationcan also be accomplished by reductive alkylation of the piperazine bytreatment with an aldehyde or ketone under reducing conditions. Examplesof suitable aldehydes include formaldehyde, acetaldehyde,propionaldehyde, butyraldehyde, isobutyraldehyde, and the like. Suitableketones include acetone, methylethylketone, and the like. Reductivealkylations are often performed under catalytic hydrogenationconditions. Other reducing agents include formic acid, sodiumborohydride, sodium cyanoborohydride, and sodium triacetoxyborohydride.This transformation can also be accomplished by acylation of thepiperazine nitrogen to form an amide and reduction of the amide to yieldthe alkylated piperazine. Examples of acylating agents include acylhalides such as acetyl chloride, propionyl chloride, pivaloyl chloride,and cyclopropylcarbonyl chloride, carboxylic acid anhydrides such asformylacetic anhydride and acetic anhydride, and carboxylic acids in thepresence of an activating agent such as dicyclohexylcarbodiimide orcarbonyldiimidazole. The resulting amides may be reduced to the tertiaryamines with reducing agents such as lithium aluminum hydride or borane.

As shown in Scheme 2, compounds of formula (II) may be prepared byreacting an appropriately substituted piperazine of formula (V) with atricyclic intermediate of formula (IV). “LG” represents a leaving groupexamples of which include NH₂, halo, OY₁, or SY₁, wherein Y₁ is loweralkyl such as methyl, ethyl, or propyl or optionally substituted phenylor OP(═O)R¹⁰. R¹⁰ can be morpholine. This reaction may conveniently beperformed with heating in a solvent such as DMSO, toluene, DMF, andN-methylpyrrolidinone.

Alternatively, as shown in Scheme 3, tricyclic amide and thioamideintermediates of formula (VI) wherein X is O or S, respectively, canreact with substituted piperazines of formula (V) to give correspondingcompounds of formula (II). This reaction is conveniently performed in apolar solvent and may be performed in the presence or absence of a Lewisacid such as TiCl₄.

In Scheme 4, compounds of formula (VIb), wherein X is S, may be preparedfrom compounds of formula (VIa), wherein X is O, by treatment with adehydrative thiolating agent in the presence of an inert solvent.Examples of such dehydrative thiolating agents include P₂S₅ andLawesson's reagent(2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide).For a description of Lawesson's reagent and its use, see M. P. Cava andM. I. Levinson, Tetrahedron, 41, 5061 (1985).

As shown in Scheme 5, tricyclic intermediates of formula (IV) can beprepared from the corresponding tricyclic amide and thioamideintermediates of formula (VI). O-alkylation of an amide of formula (VIa)(X═O) provides an iminoether of formula (I) (LG=OY₁). Suitablealkylating agents include Meerwein's reagent and methyl fluorosulfonate.ininothioethers of formula (IV), wherein LG is SY₁, may be prepared byS-alkylation of thioamides of formula (VIb) (X═S). Suitable alkylatingagents include alkyl halides, alkyl sulfonates such as methyltrifluoromethanesulfonate, Meerwein's reagent and methylfluorosulfonate. Reaction of an amide of formula (VIa) (X═O), with adehydrative halogenating agent provides an iminohalide of formula (IV),wherein LG is a halo group. Suitable dehydrative halogenating agentsinclude POCl₃, SOCl₂, PCl₃, PCl₅, PBr₃, PPh₃/Br₂, P(OPh)₃/I₂ andPPh₃/MeI.

Compounds of formula (IV) in which LG is NH₂, OY₁ or SY₁ may be preparedfrom compounds of formula (VI), wherein LG is halo, by reaction with asuitable nucleophile, such as ammonia, an alcohol, or a thiol to givecompounds of formula (IV), wherein LG is NH₂, OY₁ or SY₁, respectively.This reaction may be conveniently performed in a solvent and under basicconditions.

As shown in Scheme 6, compounds of formula (II) may also be prepared byring closure of an intermediate of formula (XIIIa). This reaction may beeffected by treatment of an amide of formula (XIIIa) with an activatingagent in the presence of an inert solvent. Examples of such activatingagents include TiCl₄, POCl₃, P₂S₅, and Lawesson's reagent.

According to Scheme 7, compounds of formula (VIa), may be prepared bycyclization of an amine compounds of formula (XIIb) in which Y₂ is OY₇or NY₈Y₉ wherein Y₇, Y₈ and Y₉ are independently, hydrogen or loweralkyl such as methyl, ethyl, or propyl.

As seen in Scheme 8, amines of formula (XIIIb) may be prepared fromcompounds of formula (XIIIc). The symbol Y₃ represents a group that maybe converted to an amino group, such as NO₂, COOH, and NHCOOY₄, whereinY₄ may be an optionally substituted alkyl such as, but not limited to,methyl, ethyl, 2-phenylethyl, t-butyl, 2-(trimethylsilyl)ethyl,2,2,2-trichloroethyl, vinyl, allyl or optionally substituted benzylgroup such as, but not limited to, benzyl, p-methoxybenzyl,p-nitrobenzyl, or diphenylmethyl.

If Y₃ is NO₂, treatment of compounds of formula (XIIIc) under reducingconditions will provide corresponding compounds of formula (XIIIb).Examples of such reducing conditions include catalytic hydrogenationconditions or SnCl₂. Compounds of formula (XIIIc), wherein Y₃ isNHCOOY₄, may be converted to the corresponding compounds of formula(XIIIb) under conditions that allow for removal of the COOY₄ group. IfY₄ is optionally substituted alkyl, such conditions may includehydrolysis under acidic or basic conditions. If Y₄ is optionallysubstituted benzyl, treatment under reducing conditions, preferablycatalytic hydrogenation conditions, provides the corresponding compoundof formula (XIIIb). If Y₄ is t-butyl, treatment with acid provides acompound of formula (XIIIb). If Y₄ is 2,2,2-trichloroethyl, reducingconditions, preferably zinc metal in acidic medium, yield a compound offormula (XIIIb). If Y₄ is 2-(trimethylsilyl)ethyl, treatment withfluoride ion yield a compound of formula (XIIIb).

Compounds of formula (XIIIb) may also be prepared by Curtiusrearrangement of the correspondent compound of formula (XIIIc) in whichY₃ is COOH. The Curtius rearrangement occurs by thermal rearrangement ofthe acylazide of formula (XIIIc) in which Y₃ is CON₃ to yield theisocyanate of formula (XIIIc) in which Y₃ is NCO. This isocyanate may behydrolyzed either directly or through the urethane in which Y₃ isNHCO₂Y₄, to yield the corresponding compound of formula (XIIIb).

According to Scheme 9, compounds of formula (IVa) in which LG is NH₂ maybe prepared by cyclization of aminonitrile compounds of formula (XIIId).

According to Scheme 10, aminonitrile compounds of formula (XIIId) may beprepared from corresponding compounds of formula (XIIIe), in the mannerdescribed for Scheme 8. Alternatively, compounds of formula (XIIId) maybe prepared by Curtius rearrangement under conditions also described forScheme 8.

As shown in Scheme 11, compounds of formula (XIIIa), wherein all groupsare defined as above, may be prepared from corresponding compounds offormula (XIIIf) in which Y₃ is a group that may be converted to an aminogroup.

According to Scheme 12, compounds of formula (XIIIf), wherein Y₃ is agroup that may be converted to an amino group as defined above, and allother groups are as defined above, may be prepared by coupling acompound of formula (V) with a compound of formula (XIIIg). Suchcoupling reactions may be performed under conditions commonly employedto form amide bonds. Coupling reagents include dicyclohexylcarbodiimide(DCC), diphenylphosphorylazide (DPPA), and1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC).

As shown in Scheme 13, compounds of formula (XIII) in which Y₃ may beNH₂ or a group that may be converted to an amino group as describedabove, Y₁₀ may be hydrogen, CN, COOY₇ or CONY₈Y₉, in which Y₇, Y₈, andY₉ may independently be hydrogen or lower alkyl, or NY₈Y₉ is the group(XVI), may be prepared by reaction of compounds of formula (XIV) inwhich Y₁₁ may be a halo group or OSO₂CF₃ with compounds of formula(XVa). This reaction may be performed under basic conditions in a polar,aprotic solvent. Suitable bases include NaH, KH, potassiumtert-butoxide, lithium hydroxide and cesium carbonate. Suitable solventsinclude DMF, N-methylpyrrolidinone, DMSO, and THF. The coupling ofcompounds of formula (XIV) with compounds of formula (XVa) to yield acompound of formula (XIII) may also be performed in the presence of ametal catalyst. Conditions for this transformation may be found inHartwig, Angew. Chem. Int. Ed. (1998) 37, 2046-2067, Wolff, et al., Acc.Chem. Res. (1998), 31, 805-818, Yang and Buchwald, J. Organomet. Chem.(1999) 576, 125-146, U.S. Pat. No. 6,271,225, U.S. Pat. No. 6,455,542,and references cited therein.

Compounds of formula (XIV) may be prepared by methods known in the art.

Alternatively as shown in Scheme 14, compounds of formula (XIII) inwhich Y₃ may be NH₂ or a group that may be converted to an amino groupas described above, Y₁₀ may be hydrogen, CN, COOY₇ or CONY₈Y₉, in whichY₇, Y₈, and Y₉ may independently be hydrogen or lower alkyl, or NY₈Y₉ isthe group (XVI), and the other groups are defined as above, may also beprepared by reaction of compounds of formula (XIVa) with compounds offormula (XV) in which Y₁₂ may be a halo group or OSO₂CF₃. This reactionmay be performed under basic conditions in a polar, aprotic solvent.Suitable bases include NaH, KH, potassium tert-butoxide, lithiumhydroxide, and cesium carbonate. Suitable solvents include DMF,N-methylpyrrolidinone, DMSO, and THF. The coupling of compounds offormula (XIVa) with compounds of formula (XV) to yield a compound offormula (XIII) may also be performed in the presence of a metalcatalyst. Conditions for this transformation may be found in Hartwig,Angew. Chem. Int. Ed. 37, 2046-2067, (1998), Wolff, et al., Acc. Chem.Res., 31, 805-818, (1998), and Yang and Buchwald, J. Organomet. Chem.576, 125-146, (1999), and references cited therein.

Compounds of formula (XIVa) may be prepared by methods known in the art.

According to Scheme 15, a compound of formula (VIa) can also be preparedby cyclization of isocyanate (XIIIh) under acidic conditions. Isocyanate(XIIIh) may be prepared from compounds of formula (XIII) in which Y₁₀ ishydrogen and Y₃ is an amino group by reaction with formicaceticanhydride and dehydration of the resulting formamide with a dehydratingagent such as POCl₃ or P₂O₅. Isocyanate (XIIIh) may also be preparedfrom compounds of formula (XIII) in which Y₁₀ is hydrogen and Y₃ is COOHby Curtius rearrangement as described before. Alternatively, a compoundof formula (IIb) may also be prepared by reaction urea (XIIIi) in thepresence of a Lewis acid. Urea (XIIIi) may be prepared by reaction ofisocyanate (XIIIh) with an amine of formula (V).

In Scheme 16, compounds of formula (VIc), the aromatic ring is thiazole,may be prepared by cyclization of intermediate of formula (XVIII) with adehydrative thiolating agent such as P₂S₅ or Lawesson's reagent.Compounds of formula (VId), the aromatic ring is an oxazole ring, may beprepared by cyclization of intermediate of formula (XVIII) with adehydrating agent such as P₂O₅ or PPh₃/Tf₂O.

According to Scheme 17, compounds of formula (XVIII) are prepared byacylation of an amine of formula (XIX). This reaction is usuallyperformed by treatment of formula of (XIX) with an acid chloride, oracid anhydride in the presence of a base in an inert solvent. Methodsfor the synthesis of compounds of formula (XIX) are known in the art;see, for example, Hagishita, et al., Bioorg. Med. Chem., 5(7),1433-1446, (1997).

As shown in Scheme 18, compounds of formula (VIe), the A ring ispyrazole, or (VIf) the A ring is pyrimidine, may also be prepared byreaction of compounds of formula (XX) with a substituted hydrazine or anamidine, respectively. Compounds of formula (XX) are prepared asdescribed in Roma, et al., Farmaco, Ed. Sci., 38, 546-558 (1983).

Methods for the preparation of compounds of formula (XVb) and formula(XVc) are known in the art and vary depending on the nature of thearomatic ring A.

The skilled artisan will recognize that substituents R² and Z in thecompounds of foumula (I) may be present in the precursor molecules offormulas (XIV), (XIVa), (XVb), and (XVc). Alternatively, thesesubstituents may be introduced at any convenient point during thesynthesis either by replacement of a hydrogen (through, for example, anelectrophilic aromatic substitution reaction) or by conversion of anexisting substituent into the substituents present in the compounds offormula (I). Examples of electrophilic aromatic substitution reactionsinclude halogenation, nitration, Friedel-Crafts acylation, andelectrophilic trifluoromethylation under conditions described in theliterature. Examples of conversion of an existing substituent into onepresent in the final compound include conversion of a Br substituentinto a substituent such as SR¹¹ or COR¹¹ by metallation with anorganolithium reagent and reaction with an electrophile such as R¹¹SSR¹¹or R¹¹COOMe. R¹¹ maybe (C₁₋₆)alkyl, fluorinated (C₁₋₆)alkyl, benzyl, oroptionally substituted phenyl” Additionally, a Br substituent can beconverted to an optionally substituted aromatic ring by reaction with anoptionally substituted phenylboronic acid in the presence of a palladiumcatalyst. Many other such functional group transformations are reportedin the literature.

General methods and specific examples of the synthesis of thesecompounds can be found in the following references:

-   Chakrabarti, et al., J. Med. Chem., 23, 878-884; (1980),-   Chakrabarti, et al., J. Med. Chem., 23, 884-889; (1980),-   Chakrabarti, et al., J. Med. Chem., 25, 1133-1140; (1982),-   Chakrabarti, et al., J. Med. Chem., 32, 2573-2582; (1989),-   Liegeois, et al., J. Med. Chem., 36, 2107-2114; (1993),-   Liegeois and Delarge, U.S. Pat. No. 5,393,752 (1995);-   Chakrabarti and Hotten, Eur. Pat. Appl., EP 354781; (1990),-   Bolton, et al., PCT Int. Appl., WO 9700252; (1997),-   Chakrabarti, et al., Eur. Pat. Appl., EP 27390; (1981),-   Tehim, et al., U.S. Pat. No. 5,602,124 (1998);-   Tehim, et al., U.S. Pat. No. 5,824,676 (1998);-   Eilingsfeld and Swybold, Ger. Offen. DE 2713573; (1978),-   Gallemaers, et al., Tetrahedron Lett., 693-694; (1976),-   Dumow and Abele, Chem. Ber., 97, 3349-3353, (1964),-   Klempier, et al., J. Heterocyclic Chem., 29, 93-95, (1992).

In Scheme 19, compounds of formula (XVd) may be prepared byregioselectively nitrating 3-bromobenzothiophene compounds to afford the2-nitro-3-bromobenzothiophene compounds of formula (XVe). Suitablenitrating conditions include nitric acid (optionally in the presence ofanother acid, such as trifluoroacetic acid, sulfiic acid, or aceticacid, or in the presence of an inert solvent such as dichloromethane orwater), fuming nitric acid, or sidium nitrite in the presence of anacid. Displacement of the 3-bromo-group with cyanide can be accomplishedusing CuCN in the presence of a polar solvent like DMF orN-methylpyrrolidinone to give compounds of formula (XVf). Reduction ofthe nitro group to the amine can be accomplished by reducing agents suchas SnCl₂/HCl, Zn/HOAc and Pd—C/H₂ to give compounds of formula (XVd) inwhich Pg is hydrogen. A protecting group may be subsequently introduced.

Compounds of formula (V) of this invention may be prepared fromcompounds of formula (XXIVb), as shown in Scheme 20, in which one of thenitrogens in the piperazine ring may be protected by an amine protectinggroup, by removal of this protecting group. In this equation, ProG₂represents an amine protecting group. Examples of such ProG₂ groupsinclude benzyl, acetyl, t-butoxycarbonyl, methanesulfonyl, and the like.Examples of additional ProG₂ groups and methods for the introduction andremoval of such groups can be found in T. W. Green, Protective Groups inOrganic Synthesis, John Wiley and Sons, Inc. (1981). In the subsequenttext, Pg₂ represents either hydrogen or an amine protecting group ProG₂.In the following text, for those intermediates containing a group Pg₂ inwhich Pg₂ is an amine protecting group, the protecting group may beremoved to give the unprotected amine. Similarly, for thoseintermediates in which Pg₂ is hydrogen, an amine protecting group may beincorporated into the intermediate. The methods for introducing andremoving these protecting groups are known in the art.

According to Scheme 21, compounds of formula (XXIVa) of this inventionmay be prepared from compounds of formula (XXVa) by removal of the amineprotecting group ProG₁. Examples of such ProG₁ amine protecting groupsinclude benzyl, acetyl, t-butoxycarbonyl, methanesulfonyl, and the like.Examples of additional ProG₁ groups and methods for the introduction andremoval of such groups can be found in T. W. Green, Protective Groups inOrganic Synthesis, John Wiley and Sons, Inc. 1981. It will be recognizedthat in some instances, in compounds of formula (XXVa), Pg₂ and ProG₁may both be protecting groups that are removed under the same reactionconditions. In those cases, deprotection of this compound will yieldcompounds of formula (V) in which R¹ is hydrogen. In compounds offormula (XXIVa), if Pg₂ is an amine protecting group, ProG₂, thenalkylation of formula (XXIVa) will yield compounds of formula (XXIV), inwhich R¹ is (C₁₋₄) alkyl optionally substituted with hydroxy, methoxy,ethoxy, or OCH₂CH₂OH.

In Scheme 22, compounds of formula (XXV), in which all groups aredefined as above, may be prepared by reduction of either aketopiperazine of formula (XXVI) or a diketopiperazine of formula XVI.Pg₁ represents either hydrogen, (C₁₋₄) alkyl optionally substituted withhydroxy, methoxy, ethoxy, or OCH₂CH₂OH, or an amine protecting groupProG₁. Suitable reducing agents for this transformation include lithiumaluminum hydride and borane. Methods for the synthesis ofketopiperazines and diketopiperazines are known in the art.

Further, as shown in Scheme 23, compounds of formula (XXVb) in which Alkis —CH₂CH₂—, —CH₂CH₂CH₂—, and —CH₂CH₂CH₂CH₂— may be prepared from asuitably protected 2-substituted piperazine of formula (XXVIII) byemploying either a Heck coupling/reduction sequence or ahydroboration/Suzuki coupling sequence. In the Heck coupling/reductionsequence, reaction of formula (XXVIII) with an arylhalide or aryltriflate in the presence of a suitable metal catalyst provides theunsaturated aryl product of formula (XXIX). For a description of theHeck reaction and its application to organic synthesis see, Whitcombe,et al., Tetrahedron, 57, 7449-7476, (2001); Herrmann, Wolfgang A., App.Homogeneous Catal. Organomet. Compd., 2, 712-732, VCH, Weinheim, Germany(Editors: Cornils, Boy; Herrmann, Wolfgang A.), (1996); and referencescited therein. Reduction of compounds of formula (XXIX) providescompounds of formula (XXVb), m=0-2. Suitable reducing conditions includecatalytic hydrogenation.

The hydroboration/Suzuki coupling sequence represents a second methodfor converting compounds of formula (XXVIII) to compounds of formula(XXVb). Reaction of formula (XXVIII) with a borane HBZZ′, in which Z andZ′ are independently H, alkyl such as methyl, ethyl, propyl, or alkoxysuch as methoxy, ethoxy, or propoxy provides an organoborane of formula(XXX). Suitable boranes HBZZ′ include, borane, trisiamylborane,catecholborane, and 9-borabicyclo[3,3,0]nonane (9-BBN). Reaction offormula (XXX) with an arylhalide or aryl triflate in the presence of asuitable catalyst provides compounds of formula (XXVb). For adescription of the Suzuki reaction and its application to organicsynthesis see, Miyaura and Suzuki, Chem. Rev., 95, 2457-2483, (1995),and references cited therein.

Compounds of formula (XXVIII)(m=0) may be prepared by the methoddescribed in Tsuda, et al., J. Org. Chem., 55, 3388-3390, (1990), andUozumi, et al., J. Org. Chem., 58, 6826-6832, (1993).

In Scheme 24 compounds of formula (XXVIII) (m=1,2) may be prepared by analkylation of formula (XXXI) with an allyl halide or a homoallyl halideand to give compounds of formula (XXXII) and reduction with lithiumaluminum hydride to give compounds of formula (XXVIII) (m=1,2).

The skilled artisan will appreciate that many of the aforementionedreactions may be performed in any convenient order. Similarly, for thosecompounds that contain an asymmetric center, the skilled artisan willrecognize that the aforementioned reactions may be performed either onpure isomers or on a mixture of isomers. The isomers may be separated atany convenient stage during the synthesis.

Pharmacological Activity

Compounds of the formula (I) have moderate to high binding affinity formultiple neurotransnitter receptors, and in particular, the dopaminereceptors. Those skilled in neuropharmacology and related disciplineshave recognized dopamine receptor binding activity as indicative ofantipsychotic, in particular, antischizophrenic properties. See P.Seeman, et al., Nature, 261, 717-718 (1976); P. Seeman, Synapse, 1, 133(1987); H. Howard, et al., 28, 39 (1993); and J. Schaus. Et al., AnnualReports in Medicinal Chemistry, 33, 1 (1998). Cloning studies havecurrently demonstrated five principal dopamine receptor subtypes thatfall into two major classes, D₁-like and D₂-like. The D₁-like classincludes the D₁ and D₅ subtypes, and the D₂-like class encompasses theD₂, D₃, and D₄ subtypes. Table 2 shows the relative binding affinity ofselected compounds of formula (I) for the D₂ receptor. The experimentalprotocol for the assay generating this data is in the Example sectionbelow. TABLE 3 Relative D₂ Receptor Binding Affinity For Compounds ofFormula (I) Comp. Affinity No. K_(i)* 59 +++ 61 ++++ 69 +++ 70 ++++ 71++++ 72 +++ 75 ++++ 76 ++++ 77 +++ 80 ++++ 85 ++++ 87 +++ 88 ++++ 90 +++92 +++ 103 +++ 109 ++++ 119 +++ 176 +++ 177 +++ 178 +++ 179 ++++ 180++++ 181 +++ 182 +++ 183 +++ 184 +++ 185 +++ 186 ++++ 187 +++ 194 ++++195 +++ 212 ++++ 219 +++ 460 ++++ 461 +++ 594 ++++ 595 +++*K_(i) is generally defined as the binding affinity constant (i.e.,dissociation constant) of an unlabeled ligand in a radioligand-bindingassay. See, for example, Neurotransmitter Receptor Binding, SecondEdition, Eds H. I. Yamamura, S. J. Enna, and M. J. Kuhar, Raven Press(1985).*++++ = <10 nM; +++ = 10-100 nM; ++ = 100-1000 nM

Using the relative K_(i) scale of Table 3, clozapine has a ++ affinityand olanzapine has a +++ affinity. Thus, many of the compounds offormula (I) exhibit D₂ receptor affinity greater than both clozapine andolanzapine.

Like clozapine and olanzapine, the compounds of formula (I) also exhibitaffinity for the 5-HT₆ receptor. Because clozapine and olanzapine havegreater efficacy in treating the cognitive disturbances of schizophreniathan typical antipsychotics (Purdon, et al., Arch Gen. Psych., 57, 249(2000)) and selective 5-HT₆ antagonists are active in models ofcognitive enhancement, this activity is desirable in an antipsychoticdrug.

Many atypical antipsychotics have a high affinity for the 5-HT_(2A)receptor. Researchers believe that high affinity for the 5-HT_(2A)receptor helps in treating the negative symptoms of schizophrenia andpreventing some of the motor side effects (H Meltzer, et al., J. Pharm.Exp. Ther. 25, 238 (1989)). However, selective 5-HT_(2A) antagonists arenot effective antipsychotics as monotherapy. Thus, 5-HT_(2A) antagonismwould likely be among the other neuroreceptor affmities of a superiorantipsychotic compound. The compounds of formula (I) exhibit a desirablelevel of 5-HT_(2A) affinity.

The compounds of formula (I) are useful for treating pathologicpsychologic conditions, especially psychosis, with minimal detrimentaladverse events. Pathologic psychological conditions which are psychosisor may be associated with psychotic features include, but are notlimited to the psychotic disorders which have been characterized in theDSM-IV-TR., Diagnostic and Statistical Manual of Mental Disorders.Revised, 4^(th) Ed., Text Revision (2000). See also DSM-IV, Diagnosticand Statistical Manual of Mental Disorders 4^(th) Ed., (1994). TheDSM-IV and DSM-IV-TR was prepared by the Task Force on Nomenclature andStatistics of the American Psychiatric Association, and providesdescriptions of diagnostic categories. The skilled artisan willrecognize that there are alternative nomenclatures, nosologies, andclassification systems for pathologic psychological conditions and thatthese systems evolve with medical scientific progress. Examples ofpathologic conditions associated with psychosis that may be treated withthe compounds of the present invention include, but are not limited to,schizophrenia, schizophreniform disorder, schizoaffective disorder,delusional disorder, brief psychotic disorder, shared psychoticdisorder, psychotic disorder due to a general medical condition,substance-induced psychotic disorder, schizotypical, schizoid, paranoidpersonality disorder, and psychotic disorder-not other specified, seeDSM-IV, Section: Schizophrenia and Other Psychotic Disorders, pages 273to 316.

Compounds of the present invention are useful in treating depression andmood disorders found in the DSM-IV, Diagnostic and Statistical Manual ofMental Disorders 4^(th) Ed., (1994) Section: Mood Disorders, pages 317to 392. Disorders include, but are not limited to, mood disorders suchas major depressive episodes, manic episode, mixed episode, hypomanicepisode; depressive disorders such as major depressive disorder,dysthymic disorder, depressive disorder not otherwise specificed;Bipolar disorders such as bipolar I disorder, bipolar II disorder,cyclothymic disorder, bipolar disorder not otherwise specified; othermood disorders such as mood disorder due to general medical conditions,substance-induced mood disorder, mood disorder not otherwise specified;and mood disorders with mild, moderate, severe without psychoticfeatures, severe with psychotic features, in partial remission, in fullremission, with catatonic features, with melancholic features, withatypical features, with postpartum onset.

One of oridinary skilled in the art would appreciate that the compoundsof the present invention would be useful in the treatment of depressiveepisodes associated with bipolar disorders, treatment of manic episodesassociated with bipolar disorders such as, but not limited to, thetreatment of the acute manic episodes associated with bipolar Idisorder.

Compounds of the present invention are useful in treating cognitivedisorders, age-related cognitive disorder, mild cognitive impairment,postconcussional disorder, mild neurocognitive disorder, anxiety(particularly including generalized anxiety disorder, panic disorder,and obsessive compulsive disorder), and migraine (including migraineheadache). These compounds are also useful in treating substancewithdrawal (including substances such as opiates, nicotine, tobaccoproducts, alcohol, benzodiazepines, cocaine, sedatives, hypnotics,caffeine, etc.). Other conditions that may be treated with the compoundsof the present invention include, but are not limited to, dementia,dementia with behavioral disturbances, movement disorders, personalitydisorders, borderline personality disorder, pervasive developmentdisoders, eating disorders, premenstrual dysphoric disorder, ticdisorders, sexual dysfunction, delirium, emesis, substance relateddisorders, impulse-control disorders, postpsychotic depressive disorderof schizophrenia, simple deteriorative disorder (simple schizophrenia),minor depressive disorder, recurrent brief depressive disorder, andmixed anxiety-depresssive disorder

Compounds of the present invention are also useful in treating thecognitive deficients associated with the above listed, but not limitedto, psychological conditions such as schizophrenia, mood disorders, andother psychotic disorders.

An effective amount can be readily determined by the attendingdiagnostician, as one skilled in the art, by the use of known techniquesand by observing results obtained under analogous circumstances. Indetermining the effective amount or dose, a number of factors areconsidered by the attending diagnostician, including, but not limitedto: the species of mammal; its size, age, and general health; thespecific disease or disorder involved; the degree of or involvement orthe severity of the disease or disorder; the response of the individualpatient; the particular compound administered; the mode ofadministration; the bioavailability characteristics of the preparationadministered; the dose regimen selected; the use of concomitantmedication; and other relevant circumstances.

The compounds of the present invention are effective over a wide dosagerange, but the actual dose administered being dependent on the conditionbeing treated. While the exact dose is administered according to thediscretion of the attending health care professional, typically, in thetreatment of adult humans, dosages of from 0.1 to 500 mg, preferablyfrom 0.25 mg to 100 mg, most preferably 0.25 mg to 50 mg per day may beused. A once a day dosage is normally sufficient, although divided dosesmay be administered. For example, for the treatment of psychoticdisorders a dose range of from 0.1 mg to 500 mg, preferably 0.25 mg to100 mg, per day is suitable.

In choosing a suitable regimen for patients suffering from psychoticconditions, compositions containing compounds of formula (I) as anactive ingredient may be formulated to provide quick, sustained ordelayed release of the active ingredient after administration to thepatient. Depending on the method of administration, compositions may beformulated as tablets, capsules, suspensions, or elixirs for oral use,or injection solutions or suppositories for parental use. Preferably thecompositions are formulated in a unit dosage form, each dosagecontaining from 0.1 mg to 500 mg, more usually 0.25 mg to 100 mg, of theactive ingredient.

A preferred formulation of the invention is a capsule or tabletcomprising 0.1 to 500 mg of active ingredient together with apharmaceutically acceptable carrier. A further preferred formulation isan injection which in unit dosage form comprises 0.1 mg to 500 mg ofactive ingredient together with a pharmaceutically acceptable diluent. Asustained release formulation is also a preferred formulation.

Pharmaceutical Formulations

While it is possible to administer a compound of formula (I) with noadditional ingredients to a patient in need thereof, it is far moredesirable to administer such a compound in the form of a pharmaceuticalcomposition. Pharmaceutical compositions containing a compound offormula (I) as an active ingredient provides control of the dosage andrate of absorption into the body and stability of the product inshipment and storage. Further, pharmaceutical formulations are moreacceptable to the patient being treated, and thus increase compliancewith a treatment program. Such compositions, comprising at least onepharmaceutically acceptable carrier, are valuable and novel because ofthe presence of the compounds of formula (I) therein. Formulation ofpharmaceutical compositions is an art unto itself, about which much hasbeen published. The compounds of the present invention may be formulatedinto pharmaceutical compositions by essentially any suitable method ofthe art including, but not limited to, the methods discussedhereinbelow.

The usual methods of formulation used in pharmaceutical science and theusual types of compositions may be used, including tablets, chewabletablets, capsules, solutions, parenteral solutions, intranasal sprays orpowders, troches, suppositories, transdermal patches and suspensions. Ingeneral, compositions contain from about 0.5% to about 50% by weight ofthe compound in total, depending on the desired dose and the type ofcomposition to be used. The amount of the compound, however, is bestdefined as the effective amount, that is, the amount of each compoundwhich provides the desired dose to the patient in need of suchtreatment. The compositions may be chosen and formulated for convenienceand economy. Any compound may be formulated in any desired form ofcomposition. Some discussion of different compositions will be provided,followed by some typical formulations.

Capsules are prepared by mixing the compound with a suitable diluent andfilling the proper amount of the mixture in capsules. The usual diluentsinclude inert powdered substances such as starch of many differentkinds, powdered cellulose, especially crystalline and microcrystallinecellulose, sugars such as fructose, mannitol and sucrose, grain floursand similar edible powders.

Tablets are prepared by direct compression, by wet granulation, or bydry granulation. Their formulations usually incorporate diluents,binders, lubricants and disintegrators as well as the compound. Typicaldiluents include, for example, various types of starch, lactose,mannitol, kaolin, calcium phosphate or sulfate, inorganic salts such assodium chloride and powdered sugar. Powdered cellulose derivatives arealso useful. Typical tablet binders are substances such as starch,gelatin and sugars such as lactose, fructose, glucose and the like.Natural and synthetic gums are also convenient, including acacia,alginates, methylcellulose, polyvinylpyrrolidine and the like.Polyethylene glycol, ethylcellulose and waxes can also serve as binders.

A lubricant is necessary in a tablet formulation to prevent the tabletand punches from sticking in the die. The lubricant is chosen from suchslippery solids as talc, magnesium and calcium stearate, stearic acidand hydrogenated vegetable oils.

Tablet disintegrators are substances which swell when wetted to break upthe tablet and release the compound. They include starches, clays,celluloses, naphth and gums. More particularly, corn and potatostarches, methylcellulose, agar, bentonite, wood cellulose, powderednatural sponge, cation-exchange resins, alginic acid, guar gum, citruspulp and carboxymethylcellulose, for example, may be used, as well assodium lauryl sulfate.

Enteric formulations are often used to protect an active ingredient fromthe strongly acidic contents of the stomach. Such formulations arecreated by coating a solid dosage form with a film of a polymer which isinsoluble in acidic environments, and soluble in basic environments.Exemplary films are cellulose acetate phthalate, polyvinyl acetatephthalate, hydroxypropyl methylcellulose phthalate and hydroxypropylmethylcellulose acetate succinate.

Tablets are often coated with sugar as a flavor and sealant, or withfilm-forming protecting agents to modify the dissolution properties ofthe tablet. The compounds may also be formulated as chewable tablets, byusing large amounts of pleasant-tasting substances such as mannitol inthe formulation, as is now well-established practice. Instantlydissolving tablet-like formulations are also now frequently used toassure that the patient consumes the dosage form, and to avoid thedifficulty in swallowing solid objects that bothers some patients.

When it is desired to administer the combination as a suppository, theusual bases may be used. Cocoa butter is a traditional suppository base,which may be modified by addition of waxes to raise its melting pointslightly. Water-miscible suppository bases comprising, particularly,polyethylene glycols of various molecular weights are in wide use, also.

Transdermal patches have become popular in recent years because oftechnological advances in matrix compositions. Typically they comprise aresinous matrix composition in which the drugs will dissolve, orpartially dissolve, which is held in contact with the skin by a filmwhich protects the composition. Many patents have appeared in the fieldrecently. Other, more complicated patch compositions are also in use,particularly those having a membrane pierced with pores through whichthe drugs are pumped by osmotic action.

EXAMPLES

The following examples illustrate aspects of this invention but shouldnot be construed as limitations thereof. The symbols and conventionsused in these examples and consistent with those used in thecontemporary chemical literature such as the Journal of the AmericanChemical Society, and Tetrahedron Letters, and contemporary literatureof other scientific disciplines as appropriate.

Chemical Compounds

Example 1 3-(S)-Phenethyl-piperazine-2,5-dione

Add sequentially, glycine methyl ester hydrochloride (4.51 g, 35.9mmol), 1-ethyl-(3-dimethyl-aminopropyl)carbodiimide hydrochloride (8.23g, 42.9 mtnol), 1-hydroxybenzotriazole monohydrate (5.81 g, 43.0 mmol),and triethylamine (10.0 mL, 71.7 mmol) to a solution of2-tert-butoxycarbonylamino-4-(S)-phenyl-butyric acid (10.0 g, 35.8 mmol)in methylene chloride (30 mL) at 0° C. Stir the mixture at roomtemperature overnight and concentrate. Partition the residue betweenethyl acetate and aqueous 2N HCl (100 mL). Wash the organic layer with10% K₂CO₃, dry (MgSO₄), and concentrate to provide the(2-tert-butoxycarbonylamino-4-(S)-phenyl-butyrylamino)-acetic acidmethyl ester as a clear oil (12.3 g, 98%): ¹H NMR (CDCl₃): δ1.45 (s,9H), 1.95 (m, 1H), 2.20 (m, 1H), 2.71 (t, 2H), 3.76 (s, 3H), 4.04 (d,2H), 4.16 (m, H), 5.00 (d, 1H), 6.57 (t, 1H), 7.17-7.32 (m, 5H).

Add trifluoroacetic acid (30 mL) to(2-tert-butoxycarbonylamino-4-(S)-phenyl-butyrylamino)-acetic acidmethyl ester (14.4 g). Stir one hour at room temperature and concentrateto afford (2-amino-4-(S)-phenyl-butyrylamino)-acetic acid methyl estertrifluoroacetate as an amber oil: ¹H NMR (D₂O): δ2.09 (m, 2H), 2.67 (m,2H), 3.61 (s, 3H), 3.82 (d, 1H), 3.91 (d, 1H), 3.95 (m, 1H), 7.13-7.28(m, 5H).

Add methanol (200 mL) and Et₃N (30 mL) to the crude trifluoroacetatesalt and reflux the solution. At 2 hours, white crystals begin to form.Reflux for an additional 2 hours and cool in an ice bath and filter.Wash the crystals with cold MeOH and hexanes to afford the titlecompound as white crystals (6.6 g, 74%): ¹H NMR (DMSO-d6): δ1.97 (m,2H), 2.63 (m, 2H), 3.70 (d, 1H), 3.75 (m, 1H), 3.81 (d, 1H), 7.13-7.32(m, 5H), 8.03 (bs, 1H), 8.32 (bs, 1H).

By the method of Example 1, the following compounds were prepared andisolated as the (S) isomer except where noted below:

No: ArAlk Data 2 CH₂(4-CH₃)Ph mp 252-253° C.; ¹H NMR(DMSO-d₆): δ2.27(s,3H), 2.77(d, 1H), 2.81(dd, 1H), 3.04(dd, 1H), 3.34(d, 1H), 4.03(m, 1H),7.04-7.10(m, 4H), 7.86(s, 1H), 8.12(s, 1H); MS(APCI)m/z(relintensity)219(100). 3 CH₂(3-CH₃)Ph ¹H NMR(DMSO-d₆): δ2.22(s, 3H),2.76(d, 1H), 2.80(dd, 1H), 3.00(dd, 1H), 3.32(d, 1H), 4.00(m, 1H), 6.91-6.95(m, 2H), 7.03(d, 1H), 7.12(t, 1H), 7.88(s, 1H), 8.11(s, 1H);MS(APCI)m/z(rel intensity)219(100). 4 CH₂(2-F)Ph mp 227° C.; ¹HNMR(DMSO-d₆): δ2.99(m, 2H), 3.15(d, 1H), 3.36(dd, 1H), 4.00(m, 1H),6.91-7.36(m, 4H), 7.88(s, 1H), 8.10(s, 1H); MS(APCI)m/z(relintensity)223 (100). 5 CH₂(3-F)Ph ¹H NMR(DMSO-d₆): δ2.87(dd, 1H),2.98(d, 1H), 3.06(dd, 1H), 3.42(d, 1H), 4.06(m, 1H), 6.93-7.04(m, 3H),7.27(m, 1H), 7.92(s, 1H), 8.12(s, 1H); MS(APCI)m/z (relintensity)223(100). 6 CH₂(4-F)Ph ¹H NMR(DMSO-d₆): δ2.87(dd, 1H), 2.88(d,1H), 3.04(dd, 1H), 3.38(d, 1H), 4.02(m, 1H), 7.07(t, 2H), 7.14(dd, 2H),7.87(s, 1H), 8.11(s, 1H); MS(APCI)m/z(rel intensity)223(100). 7CH₂(2-Cl)Ph ¹H NMR(DMSO-d₆): δ.08(dd, 1H), 3.19(dd, 1H), 3.48(m, 2H),3.99(m, 1H), 7.27-7.31(m, 3H), 7.43(m, 1H), 8.06(s, 2H); MS(APCI)m/z(relintensity)239(100), 241 (36). 8 CH₂(3-Cl)Ph ¹H NMR(DMSO-d₆): δ2.90(dd,1H), 3.06(d, 1H), 3.08 (dd, 1H), 3.49(d, 1H), 4.10(m, 1H), 7.15(m, 1H),7.25(s, 1H), 7.32(m, 2H), 8.01(s, 1H), 8.22(s, 1H); MS(APCI) m/z(relintensity)239(100), 241(36). 9 CH₂(4-Cl)Ph mp 259-262° C.; ¹HNMR(DMSO-d₆): δ2.89(dd, 1H), 3.01(d, 1H), 3.09(dd, 1H), 3.46(d, 1H),4.08(m, 1H), 7.19(d, 2H), 7.35(d, 2H), 7.94(s, 1H), 8.17(s, 1H); MS(APCI)m/z(rel intensity)239(100), 241(36). 10 CH₂(3-CF₃)Ph ¹HNMR(DMSO-d₆): δ2.98(dd, 1H), 2.99(d, 1H), 3.16(dd, 1H), 3.46(d, 1H),4.12(m, 1H), 7.43-7.60(m, 4H), 7.96(s, 1H), 8.20(s, 1H): ms(APCI)m/z(relintensity) 273(100). 11 CH₂(2-CF₃)Ph ¹H NMR(DMSO-d₆): δ3.06(dd, 1H),3.20(dd, 1H), 3.55(dd, 1H), 3.77(d, 1H), 3.89(m, 1H), 7.41-7.46(m, 2H),7.59(t, 1H), 7.67(d, 1H), 8.03(s, 1H), 8.09(s, 1H); MS (APCI)m/z(relintensity)273(100). 12 CH₂(2-OCH₃)Ph mp 222-224° C.: ¹H NMR(DMSOd₆):δ2.90(dd, 1H), 3.06(dd, 1H), 3.21(d, 1H), 3.41(d, 1H), 3.75(s, 3H),3.93(m, 1H), 6.86(t, 1H), 6.95(d, 1H), 7.09(d, 1H), 7.24(t, 1H), 7.87(s,1H), 7.92(s, 1H); MS(APCI)m/z(rel intensity)235(100). 13 CH₂(3-OCH₃)Phmp 204-206° C.; ¹H NMR(DMSO-d₆): δ2.86(dd, 1H), 2.86(d, 1H), 3.07(dd,1H), 3.38(d, 1H), 3.41(s, 3H), 4.05(m, 1H), 6.73(d, 1H), 6.74(s, 1H),6.83(d, 1H), 7.19(t, 1H), 7.91(s, 1H), 8.13(s, 1H); MS(APCI)m/z(relintensity)235(100). 14 CH₂(4-OCH₃)Ph ¹H NMR(DMSO-d₆): δ2.73(d, 1H),2.75(dd, 1H), 2.97(dd, 1H), 3.31(d, 1H), 3.68(s, 3H), 3.96(m, 1H),6.79(d, 2H), 7.02(d, 2H), 7.82(s, 1H), 8.06(s, 1H); MS(APCI) m/z(relintensity)235(100). 15 CH₂(3,5-diCl)Ph ¹H NMR(DMSO-d₆): δ2.86(dd, 1H),3.04(dd, 1H), 3.20(d, 1H), 3.50(d, 1H), 4.07(m, 1H), 7.14(d, 1H),7.39(s, 1H), 7.51(d, 1H), 7.97(s, 1H), 8.15(s, 1H); MS(APCI) m/z(relintensity)273(100), 275(60). 16 CH₂(indol-3yl) mp 262-271° C.; ¹HNMR(DMSO-d₆): δ2.74(d, 1H), 2.98(dd, 1H), 3.19(dd, 1H), 3.21(d, 1H),3.98(m, 1H), 6.93(t, 1H), 7.02(t, 1H), 7.03(s, 1H), 7.29(d, 1H), 7.50(d,1H), 7.72(s, 1H), 8.05(s, 1H); MS(APCI)m/z(rel intensity)244(100). 17CH₂(thiophen-2-yl) ¹H NMR(DMSO-d₆): δ3.00(dd, 1H), 3.07(d, 1H), 3.28(dd,1H), 3.45(d, 1H), 4.05(t, 1H), 6.80(s, 1H), 6.91(d, 1H), 7.40(d, 1H),7.91(s, 1H), 8.17(s, 1H); MS(APCI) m/z(rel intensity)211(100). 18CH₂(benzo(b)thiophen-3-yl) ¹H NMR(DMSO-d₆): δ3.04(d, 1H), 3.17(dd, 1H),3.29(dd, 1H), 3.37(d, 1H), 4.08(s, 1H), 7.30-7.36(m, 2H), 7.37(s, 1H),7.80(d, 1H), 7.87(s, 1H), 7.92(d, 1H), 8.15(s, 1H); MS(APCI)m/z(relintensity)261(100). 20 CH₂(naphthalene-1-yl) ¹H NMR(DMSO-d₆): δ3.11(d,1H), 3.35(d, 1H), 3.44(dd, 1H), 3.50(dd, 1H), 4.07(m, 1H), 7.37(d, 1H),7.44(t, 1H), 7.48-7.57(m, 2H), 7.84(d, 1H), 7.92(d, 1H), 7.94(s, 1H),8.10(s, 1H), 8.13(d, 1H); MS(APCI)m/z(rel intensity)255(100). 21CH₂(naphthalene-2-yl) ¹H NMR(DMSO-d₆): δ2.83(d, 1H), 3.09(dd, 1H),3.26(dd, 1H), 3.36(d, 1H), 4.16(m, 1H), 7.36(d, 1H), 7.45-7.52(m, 2H),7.69(s, 1H), 7.80-7.91(m, 4H), 7.95(s, 1H), 8.27(s, 1H); MS(APCI)m/z(relintensity)255 (100). 23 CH₂(3,5-Di-F)Ph ¹H NMR(DMSO-d₆): δ2.90(dd, 1H),3.23(d, 1H), 3.52(d, 1H), 3.61(dd, 1H), 4.09(m, 1H), 6.86(d, 2H),7.07(t, 1H), 8.00(s, 1H), 8.13(s, 1H); MS(APCI)m/z(relintensity)241(100). 23a CH₂(4-Ph)Ph ¹H NMR(DMSO-d₆)δ2.94(dd, 1H),3.06-3.18(m, 2H), 3.43(d, 1H), 4.11(m, 1H), 7.23(d, 2H), 7.36(t, 1H),7.44(t, 2H), 7.61(d, 2H), 7.66(d, 2H), 7.94(bs, 1H), 8.20(bs, 1H).

Example 24 2-(S)-Phenethyl-piperazine

Add 3-(S)-phenethyl-piperazine-2,5-dione (2.5 g, 11 mmol) portionwise tolithium aluminum hydride (1.75 g, 46 mmol) in THF (46 mL). Reflux theresulting suspension for an hour and cool to 0° C. Add sodium sulfatedecahydrate careflilly until hydrogen evolution ceases and stir themixture for an additional three hours at room temperature and filter.Wash the solids with THF several times. Combine the filtrates,concentrate, and recrystallize the residue with THF/pentane to afford2-(S)-phenethyl-piperazine as white crystals (1.9 g, 90%): mp 114-115°C.; ¹H NMR (CDCl₃): δ1.58-1,70 (m, 2H), 2.41 (dd, 1H), 2.58-3.02 (m,8H), 7.16-7.30 (m, 5H); MS (APCI) m/z (rel intensity) 191 (100).

By a similar method to Example 24, using the appropriate startingmaterials, the following piperazines were prepared and isolated as the(S) isomer except where noted below:

No: ArAlk Data 25 CH₂Ph mp 65-67° C.; ¹H NMR(CDCl₃): δ2.47-2.57(m, 2H),2.67- 3.00(m, 7H), 7.16-7.30(m, 5H); MS(APCI)m/z(rel intensity)177(100). 26 CH₂(4-Ph)Ph mp 129-134° C.; ¹H NMR(CDCl₃)δ2.51-2.59(m, 2H),2.68- 3.03(m, 7H), 7.23(d, 2H), 7.31(t, 1H), 7.42(t, 2H), 7.57(d, 2H),7.59(d, 2H); MS(ESIpos)m/z(rel intensity)253.3(100). 33CH₂(naphthalen-1-yl) ¹H NMR(CDCl₃): δ2.58-2.67(m, 2H), 2.82(ddd, 1H),2.85- 2.95(m, 3H), 3.02(m, 1H), 3.05(m, 1H), 3.22(dd, 1H), 7.37- 7.43(m,2H), 7.47-7.54(m, 2H), 7.75(d, 1H), 7.86(m, 1H), 8.07(m, 1H);MS(APCI)m/z(rel intensity)227(100). 34 CH₂(naphthalen-2-yl) ¹HNMR(CDCl₃): δ2.57(dd, 1H), 2.65-2.99(m, 7H), 3.02(dd, 1H), 7.33(d, 1H),7.42-7.50(m, 2H), 7.66(s, 1H), 7.75- 7.83(m, 3H); MS(APCI)m/z(relintensity)227(100). 35 CH₂(3-F)Ph ¹H NMR(CDCl₃): δ2.57-2.46(ddd, 1H),2.81-2.65(m, 4H), 3.02-2.82(m, 4H), 7.00-6.88(m, 3H), 7.29-7.21(m, 1H);MS (APCI)m/z(rel intensity)195.3(100). 36 CH₂(2-F)Ph ¹H NMR(CDCl₃):δ2.49(dd, 1H), 2.58(dd, 1H), 2.98-2.84(m, 3H), 3.02-2.82(m, 4H),7.09-6.97(m, 2H), 7.24-7.17(m, 2H); MS(APCI)m/z(relintensity)195.3(100). 37 CH₂(3-CF₃)Ph ¹H NMR(CDCl₃): δ2.50(dd, 1H),2.61(dd, 1H), 2.81-2.69(m, 3H), 2.98-2.83(m, 4H), 7.54-7.36(m, 4H);MS(APCI) m/z(rel intensity)245.3(100). 38 (R)—CH₂Ph ¹H NMR(CDCl₃):δ2.47-2.57(m, 2H), 2.67-3.00(m, 7H), 7.16-7.30(m, 5H); MS(APCI)m/z(relintensity)177(100). 39 CH₂(3-CH₃)Ph mp 58-63° C.; ¹H NMR(CDCl₃):δ2.33(s, 3H), 2.50(ddd, 2H), 2.67(dd, 1H), 2.94-2.70(m, 5H), 2.98(dd,1H), 7.06- 6.97(m, 3H), 7.19(t, 1H); MS(APCI)m/z(rel intensity)191.3(100). 40 CH₂(indol-3-yl) mp 45-58° C.; ¹H NMR(CDCl₃): δ2.54(dd, 1H),3.02-2.63(m, 7H), 3.06(dd, 1H), 7.05(bs, 1H), 7.11(dt, 1H), 7.18(dt,1H), 7.36(dd, 1H), 7.65(d, 1H), 8.06(bs, 1H) 41CH₂(benzo(b)thiophen-3-yl) ¹H NMR(CDCl₃): δ2.57(dd, 1H), 2.99-2.76(m,7H), 3.08(dd, 1H), 7.15(s, 1H), 7.19(s, 1H), 7.35-7.25(m, 1H), 7.82-7.70(m, 2H), MS(APCI)m/z(rel intensity)233.2(100). 42 CH₂(4-F)Ph ¹HNMR(CDCl₃): δ2.46(ddd, 2H), 2.63(dd, 1H), 2.84-2.67(m, 3H), 2.95-2.85(m,3H), 6.98-6.92(m, 2H), 7.14-7.04(m, 2H); MS(APCI)m/z(relintensity)195.3(100). 43 CH₂(4-OCH₃)Ph mp 76-80° C.; ¹H NMR(CDCl₃):δ2.45(ddd, 2H), 2.61(dd, 1H), 2.82-2.65(m, 3H), 2.91-2.85(m, 2H),2.94(dd, 1H), 3.76(s, 3H), 6.81(d, 2H), 7.09(d, 2H); MS(APCI)m/z(relintensity)207.3(100). 46 CH₂(4-CH₃)Ph mp 64-68° C.; ¹H NMR(CDCl₃):δ2.32(s, 3H), 2.47(dd, 1H), 2.49(dd, 1H), 2.65(dd, 1H), 2.68(dd, 1H),2.73(dd, 1H), 2.80(m, 1H), 2.86-2.93(m, 2H), 7.07-7.13(m, 4H); MS(APCI)m/z(rel intensity)191(100). 47 CH₂(4-Cl)Ph mp 77-81° C.; ¹H NMR(CDCl₃):δ2.45(ddd, 2H), 2.61(dd, 1H), 2.82-2.65(m, 3H), 2.91-2.85(m, 2H),2.94(dd, 1H), 6.81(d, 2H), 7.09(d, 2H); MS(APCI)m/z(rel intensity)211.3(100). 48 CH₂(2-OCH₃)Ph ¹H NMR(CDCl₃): δ2.49(dd, 1H), 2.53(dd, 1H),2.80-2.68(m, 3H), 2.98-2.87(m, 4H), 3.81(s, 3H), 6.90-6.83(m, 2H),7.23-7.12(m, 2H); MS(APCI)m/z(rel intensity)207.3(100). 49 CH₂(3-OCH₃)Phmp 57-61° C.; ¹H NMR(CDCl₃); δ2.49(dd, 1H), 2.52(dd, 1H), 2.78-2.65(m,3H), 2.94-2.79(m, 3H), 2.97(dd, 1H), 3.80(s, 3H), 6.81-6.74(m, 3H),7.21(ddd, 1H); MS(APCI)m/z(rel intensity)207.3(100). 50 CH₂(2-Cl)Ph ¹HNMR(CDCl₃): δ2.53(dd, 1H), 2.65(dd, 1H), 2.81-2.70(m, 2H), 2.99-2.83(m,5H), 7.27-7.14(m, 3H), 7.38-7.35(m, 1H); MS(APCI)m/z(relintensity)211(100), 213(36). 51 CH₂(3-Cl)Ph ¹H NMR(CDCl₃): δ2.49(dd,1H), 2.51(dd, 1H), 2.67(m, 1H), 2.77-2.71(m, 2H), 2.99-2.78(m, 4H),7.10-7.07(m, 1H), 7.26-7.19(m, 3H); MS(APCI)m/z(rel intensity)211(100),213(38). 52 CH₂(3,4-Di-Cl)Ph ¹H NMR(CDCl₃): δ2.49(dd, 1H), 2.97-2.73(m,7H), 3.00(dd, 1H), 6.86-6.83(m, 1H), 6.94(dd, 1H), 7.17(dd, 1H); MS(APCI)m/z(rel intensity)245(100). 53 CH₂(thiophen-2-yl) ¹H NMR(CDCl₃):δ2.49(dd, 1H), 2.51(dd, 1H), 2.67(m, 1H), 2.77-2.71(m, 2H), 2.99-2.78(m,4H), 7.10-7.07(m, 1H), 7.26-7.19(m, 2H); MS(APCI)m/z(relintensity)183(100). 55 CH₂(2-CF₃)Ph ¹H NMR(CDCl₃): δ2.53-2.46(m, 1H),2.78-2.66(m, 3H), 2.96-2.84(m, 5H), 7.31(t, 1H), 7.37(d, 1H), 7.46(t,1H), 7.63(d, 1H): MS(APCI)m/z(rel intensity)183(100). 57 CH₂(3,5-Di-F)Ph¹H NMR(CDCl₃): δ2.48(ddd, 1H), 2.53(dd, 1H), 2.66(dd, 1H), 2.72-2.78(m,2H), 2.84(m, 1H), 2.88-2.98(m, 3H), 6.67(t, 1H), 6.73(d, 2H);MS(APCI)m/z(rel intensity)213(100).

Example 58 2-(S)-(4-Bromo-benzyl)-pipierazine

Add dropwise a 1M solution of BH₃.THF (183 mL, 183 mmol) to3-(S)-(4-bromo-benzyl)-piperazine-2,5-dione (6.5 g, 23 mmol) in 100 mLof dry THF at ambient temperature. Stir for an hour then heat to refluxfor two days and cool down to 0° C. Add slowly a 12% hydrobromic acidsolution in acetic acid and stir overnight. Isolate the precipitate,wash it with ethyl acetate and hexanes and dry it to yield thedi-hydrobromic salt as a white solid. Add to this solid a saturatedsodium bicarbonate in water and extract with a solution ofdichloromethane and isopropyl alcohol (75/25). Dry over magnesiumsulfate and evaporate the solvent to yield the title compound (4.3 g,73%) as a white powder: mp=91-93° C.; ¹H NMR (CDCl₃): δ2.45-2.52 (m,2H), 2.64 (dd, 1H), 2.68-2.75 (m, 2H), 2.82 (m, 1H), 2.88-2.97 (m, 3H),7.08 (d, 2H), 7.42 (d, 2H); MS (APCI) m/z (rel intensity) 255 (100), 257(100).

Example 592-Methyl-10-(S)-(3-phenethyl-piperazin-1-yl)-4H-3-thia-4,9-diazabenzo[f]azulene

Heat a suspension of2-methyl-4H-3-thia4,9-diaza-benzo[f]-azulen-10-ylamine hydrochloride(466 mg, 1.75 mmol) and 2-(S)-phenethyl-piperazine (1.0 g, 5.3 mmol) inDMSO (2.5 mL) and toluene (10 mL) at reflux for 48 hours. Evaporate thetoluene under vacuo and pour the resulting solution into water (10 mL).Purify the resulting brown solid by flash chromatography eluting withmethylene chloride/methanol (95:5) to give2-methyl-10-(3-(S)-phenethyl-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azuleneas a yellow solid (478 mg, 65%): mp 75-84° C.; ¹H NMR(CDCl₃): δ1.76 (m,2H), 2.31 (s, 3H), 2.60 (dd, 1H), 2.71 (m, 2H), 2.80 (m, 1H), 2.92 (m,2H), 3.04 (m, 1H), 3.96 (m, 1H), 4.12 (m, 1H), 4.91 (s, 1H), 6.29 (s,1H), 6.60 (d, 1H), 6.89 (t, 1H), 6.96 (t, 1H), 7.03 (d, 1H), 7.15-7.30(m, 5H); MS (APCI) m/z (rel intensity) 403 (100).

By a method similar to Example 59, using the appropriate startingmaterial, the following compounds were prepared and isolated as the (S)isomer except where noted below:

No: ArAlk Data 61 CH₂Ph mp 169-170° C.; ¹H NMR(CDCl₃): δ2.26(s, 3H),2.61(dd, 1H), 2.68(dd, 1H), 2.71-2.87(m, 2H), 2.92-3.03(m, 3H), 3.99(d,1H), 4.09(d, 1H), 4.93(s, 1H), 6.20(s, 1H), 6.59(d, 1H), 6.87(t, 1H),6.96(t, 1H), 7.03(d, 1H), 7.20-7.33(m, 5H); MS (APCI)m/z(relintensity)389(100). 70% yield. 62 CH₂(4-O—CH₂CH═C(CH₃)₂)_(Ph) mp 86-97°C.; ¹H NMR(CDCl₃)δ1.74(s, 3H), 1.80(s, 3H), 2.26(s, 3H), 2.57(dd, 1H),2.67(dd, 1H), 2.74(dd, 1H), 2.84(dd, 1H), 3.04-2.92(m, 3H), 4.00(d, 1H),4.08(d, 1H), 4.49(d, 2H), 4.95(s, 1H), 5.50(m, 1H), 6.20(d, 1H),6.60(dd, 1H), 6.89-6.84(m, 3H), 6.96(dt, 1H), 7.02(dd, 1H), 7.13(d, 2H);MS(APCI)m/z(rel intensity)473.5(100). 34% yield. 63 CH₂(3,4-OCH₂O—)Ph mp123-130° C.; ¹H NMR(CDCl₃)δ2.26(s, 3H), 2.55(dd, 1H), 2.67(dd, 1H),2.72(dd, 1H), 2.85(dd, 1H), 3.04-2.92(m, 3H), 4.00(d, 1H), 4.08(d, 1H),4.98(s, 1H), 5.94(d, 2H), 6.21(dd, 1H), 6.61(dt, 1H), 6.68(dt, 1H),6.77-6.73(m, 2H), 6.87(ddd, 1H), 6.97(ddd, 1H), 7.02(dd, 1H);MS(APCI)m/z(rel intensity)433.5(100). 43% yield. 64 CH₂(3,4-Di-OCH₃)Phmp 127-139° C.; ¹H NMR(CDCl₃)δ2.26(s, 3H), 2.55(dd, 1H), 2.68(dd, 1H),2.76(dd, 1H), 2.82(dd, 1H), 3.04-2.92(m, 3H), 3.87(s, 3H), 3.88(s, 3H),4.00(d, 1H), 4.15(d, 1H), 4.98(s, 1H), 6.22(d, 1H), 6.60(dd, 1H),6.83-6.73(m, 3H), 6.87(dt, 1H), 6.97(dt, 1H), 7.02(dd, 1H);MS(APCI)m/z(rel intensity) 449.5(100). 47% yield. 65 CH₂(4-iPr)Ph mp78-83° C.: ¹H NMR(CDCl₃)δ1.24(d, 6H), 2.27(s, 3H), 2.57(dd, 1H),2.69(dd, 1H), 2.76(dd, 1H), 2.79-3.02(m, 5H), 3.98(m, 1H), 4.11(m, 1H),4.97(s, 1H), 6.23(s, 1H), 6.60(d, 1H), 6.86(t, 1H), 6.96(t, 1H), 7.01(d,1H), 7.14-7.18(m, 4H); MS(APCI)m/z(rel intensity)431(100). 66% yield. 66CH₂(4-OPh)Ph ¹H NMR(CDCl₃)δ2.27(s, 3H), 2.61(dd, 1H), 2.67(dd, 1H),2.76(dd, 1H), 2.86(ddd, 1H), 2.93-3.05(m, 3H), 3.99(m, 1H), 4.09(m, 1H),4.96(s, 1H), 6.22(s, 1H), 6.59(d, 1H), 6.86(t, 1H), 6.94-7.02(m, 5H),7.10(t, 1H), 7.19(d, 2H), 7.33(t, 2H); MS(APCI)m/z(relintensity)481(100). Product isolated as an orange powder. 67CH₂(naphthalene-2-yl) mp 101-119° C.; ¹H NMR(CDCl₃): δ2.32(s, 3H),2.70-2.88(m, 3H), 2.98(m, 3H), 3.10(m, 1H), 4.00(m, 1H), 4.17(m, 1H),4.93(s, 1H), 6.28(s, 1H), 6.60(d, 1H), 6.86(t, 1H), 6.96(t, 1H), 7.02(d,1H), 7.39(d, 1H), 7.32(m, 2H), 7.70(s, 1H), 7.81(m, 3H); MS(APCI)m/z(relintensity)439(100). 27% yield. 68 CH₂(naphthalene-1-yl) mp 106-116° C.;¹H NMR(CDCl₃): δ2.30(s, 3H), 2.74-2.83(m, 2H), 2.94-3.06(m, 3H), 3.18(m,1H), 3.30(dd, 1H), 3.96(m, 1H), 4.15(m, 1H), 4.92(s, 1H), 6.14(s, 1H),6.60(d, 1H), 6.86(t, 1H), 7.96(t, 1H), 7.03(d, 1H), 7.40(m, 2H),7.47-7.56(m, 2H), 7.77(d, 1H), 7.88(d, 1H), 8.09(d, 1H); MS(APCI)m/z(rel intensity)439(100). 36% yeild. 69 CH₂(4-CH₃)Ph mp 92-101° C.; ¹HNMR(CDCl₃): δ2.26(d, 3H), 2.33(s, 3H), 2.57(dd, 1H), 2.68(dd, 1H),2.86-2.74(m, 2H), 3.03-2.91(m, 3H), 4.00(bd, 1H), 4.10(bd, 1H), 4.97(s,1H), 6.21(d, 1H), 6.60(dd, 1H), 6.87(dt, 1H), 6.96(dt, 1H), 7.02(dd,1H), 7.12(m, 4H); MS(APCI)m/z(rel intensity)403.3(100). 80% yield. 70CH₂(3-CH₃)Ph mp 80-97° C.; ¹H NMR(CDCl₃): δ2.26(d, 3H), 2.34(s, 3H),2.57(dd, 1H), 2.69(dd, 1H), 2.87-2.74(m, 2H), 3.03-2.93(m, 3H), 3.96(bd,1H), 4.41(bd, 1H), 4.93(s, 1H), 6.21(d, 1H), 6.60(dd, 1H), 6.87(dt, 1H),6.96(dt, 1H), 7.06-7.00(m, 4H), 7.23-7.17(m, 1H); MS(APCI)m/z(relintensity)403.3(100). 55% yield. 71 CH₂(2-F)Ph mp 84-102° C.; ¹HNMR(CDCl₃): δ2.24(s, 3H), 2.74-2.65(m, 2H), 2.86-2.79(m, 1H), 2.88(dd,1H), 3.10-2.92(m, 3H), 4.02(t, 2H), 4.96(s, 1H), 6.19(d, 1H), 6.59(dd,1H), 6.86(dt, 1H), 6.96(dt, 1H), 7.11-6.99(m, 3H), 7.26-7.19(m, 2H); MS(APCI)m/z(rel intensity)407.4(100). 64% yield. 72 CH₂(3-F)Ph mp 87-99°C.; ¹H NMR(CDCl₃): δ2.26(s, 3H), 2.70-2.59(m, 2H), 2.90-2.75(m, 2H),3.05-2.92(m, 3H), 3.98(d, 1H), 4.09(d, 1H), 4.96(s, 1H), 6.21-6.19(m,1H), 6.60(dd, 1H), 6.87(dt, 1H), 7.04-6.91(m, 5H), 7.30-7.24(m, 1H);MS(APCI)m/z(rel intensity)407.4(100). 54% yield. 73 CH₂(4-F)Ph mp 86-99°C.; ¹H NMR(CDCl₃): δ2.23(s, 3H), 2.69-2.57(m, 2H), 2.74(dd, 1H),2.83(dd, 1H), 3.12-2.91(m, 3H), 3.97(d, 1H), 4.05(d, 1H), 4.97(bs, 1H),6.16(d, 1H), 6.58(dd, 1H), 6.85(dt, 1H), 7.01-6.92(m, 4H), 7.19-7.14(m,2H); MS (APCI)m/z(rel intensity)407.4(100). 73% yield. 74 CH₂(2-CF₃)Phmp 103-108° C.; ¹H NMR(CDCl₃): δ2.25(s, 3H), 2.67(dd, 1H), 2.72-2.82(m,2H), 2.87(dd, 1H), 2.93-3.07(m, 3H), 4.01(m, 2H), 4.93(s, 1H), 6.19(s,1H), 6.59(d, 1H), 6.86(t, 1H), 6.94-7.01(m, 2H), 7.34(t, 1H), 7.40(d,1H), 7.49(t, 1H), 7.67(d, 1H); MS(APCI)m/z(rel intensity)457(100). 54%yield. 75 CH₂(2-OCH₃)Ph mp 95-109° C.; ¹H NMR(CDCl₃): δ2.23(s, 3H),2.66(dd, 1H), 2.71(dd, 1H), 2.90-2.80(m, 2H), 3.09-2.93(m, 3H), 3.83(s,3H), 4.06-3.98(m, 2H), 4.98(bs, 1H), 6.17(s, 1H), 6.60(dd, 1H),6.92-6.84(m, 3H), 6.96(dt, 1H), 7.02(dd, 1H), 7.18(dd, 1H), 7.22(dt,1H); MS(APCI)m/z(rel intensity)419.4(100). 54% yield. 76 CH₂(3-OCH₃)Phmp 96-109° C.; ¹H NMR(CDCl₃): δ2.24(s, 3H), 2.64-2.91(m, 4H),3.12-3.01(m, 3H), 3.79(s, 3H), 4.01(bd, 1H), 4.09(bd, 1H), 5.06(bs, 1H),6.17(s, 1H), 6.60(d, 1H), 6.89-6.75(m, 4H), 6.95(t, 1H), 7.02(d, 1H),7.21(dt, 1H); MS(APCI)m/z (rel intensity)419.4(100). 25% yield. 77CH₂(4-OCH₃)Ph mp 85-98° C.: ¹H NMR(CDCl₃): δ2.23(s, 3H), 2.56(dd, 1H),2.66(dd, 1H), 2.72(dd, 1H), 2.81(dt, 1H), 3.02-2.91(m, 3H), 3.77(s, 3H),3.98(d, 1H), 4.06(d, 1H), 4.98(bs, 1H), 6.17(s, 1H), 6.58(dd, 1H),6.87-6.80(m, 3H), 6.94(dt, 1H), 6.99(dd, 1H), 7.15-7.10(m, 2H);MS(APCI)m/z(rel intensity)419.5 (100). 17% yield. 78 CH₂(34,-Di-Cl)Ph mp108-114° C.; ¹H NMR(CDCl₃): δ2.26(s, 3H), 2.58(dd, 1H), 2.66(dd, 1H),2.74(dd, 1H), 2.85(ddd, 1H), 2.93-3.03(m, 3H), 3.96(m, 1H), 4.07(m, 1H),4.97(s, 1H), 6.19(s, 1H), 6.60(d, 1H), 6.86(t, 1H), 6.94-7.03(m, 2H),7.07(d, 1H), 7.36-7.42(m, 2H; MS(APCI)m/z(rel intensity)457(100),457(68). 48% yield. 79 CH₂(indol-3-yl) mp 146-158° C.; ¹H NMR(CDCl₃):δ2.16(s, 3H), 2.84-2.68(m, 3H), 3.05-2.88(m, 3H), 3.17-3.07(m, 1H),3.95(d, 1H), 4.14(bs, 1H), 5.07(bs, 1H), 6.15(bs, 1H), 6.57(d, 1H),6.84(t, 1H), 6.94(t, 1H), 7.06-7.00(m, 2H), 7.09(t, 1H), 7.17(t, 1H),7.33(d, 1H), 7.63(d, 1H), 8.26(bs, 1H); MS(APCI)m/z (relintensity)428.4(100). 55% yield. 80 CH₂(thiophen-2-yl) mp 95-104° C.; ¹HNMR(CDCl₃): δ2.27(s, 3H), 2.68(dd, 1H), 2.84-2.90(m, 2H), 2.94-3.04(m,4H), 3.98(m, 1H), 4.10(m, 1H), 5.04(bs, 1H), 6.24(s, 1H), 6.59(d, 1H),6.86(m, 2H), 6.93-6.97(m, 2H), 7.02(d, 1H), 7.17(d, 1H); MS(APCI)m/z(rel intensity)395(100). 10% yield. 81 CH₂(benzo(b)thiophen-3-yl) mp115-124° C.; ¹H NMR(CDCl₃): δ2.20(s, 3H), 2.73(dd, 1H), 2.82(dd, 1H),3.05-2.85(m, 4H), 3.22-3.14(m, 1H), 3.95(d, 1H), 4.16(d, 1H), 4.97(bs,1H), 6.14(d, 1H), 6.57(dd, 1H), 6.85(dt, 1H), 6.95(dt, 1H), 7.01(dd,1H), 7.22(s, 1H), 7.34(dd, 1H), 7.38(dd, 1H), 7.79(dd, 1H), 7.85(dd,1H); MS (APCI)m/z(rel intensity)445.4(100). 28% yield. 82CH₂(3-O-i-Pr—Ph) ¹H NMR(CDCl₃)δ1.33(dd, 6H), 2.26(s, 3H), 2.55-3.01(m,7H), 3.98(d, 1H), 4.11(d, 1H), 4.55(m, 1H), 4.93(s, 1H), 6.21(s, 1H),6.59(d, 1H), 6.77(m, 3H), 6.87(t, 1H), 6.98(m, 2H), 7.21(t, 1H);MS(ESI)m/z(rel intensity)447(100). Product isolated as a yellow solid.83 (R)CH₂Ph mp 84-98° C.: ¹H NMR(CDCl₃)δ2.26(s, 3H), 2.61(dd, 1H),2.68(dd, 1H), 2.71-2.87(m, 2H), 2.92-3.03(m, 3H), 3.99(d, 1H), 4.09(d,1H), 4.93(s, 1H), 6.20(s, 1H), 6.59(d, 1H), 6.87(t, 1H), 6.96(t, 1H),7.03(d, 1H), 7.20-7.33(m, 5H); MS (APCI)m/z(rel intensity)389(100). 83%yield. 84 CH₂(2,4-di-OCH₃)Ph ¹H NMR(CDCl₃)δ2.24(s, 3H), 2.55(dd, 1H),2.65(m, 1H), 2.75(dd, 1H), 2.84(ddd, 1H), 2.91-3.04(m, 3H), 3.80(s, 6H),3.99-4.03(m, 2H), 4.95(s, 1H), 6.19(s, 1H), 6.42(d, 1H), 6.46(s, 1H),6.60(d, 1H), 6.86(t, 1H), 6.96(t, 1H), 7.02(d, 1H), 7.06(d, 1H);MS(APCI)m/z(rel intensity)449(100). Product isolated as a a yellowsolid. 85 CH₂(4-Cl)Ph mp 91-108° C.; ¹H NMR(CDCl₃): δ2.26(s, 3H),2.61(dd, 1H), 2.66(dd, 1H), 2.75(dd, 1H), 2.88-2.81(m, 1H), 3.03-2.91(m,3H), 3.99(bd, 1H), 4.07(bd, 1H), 4.95(bs, 1H), 6.17(d, 1H), 6.60(dd,1H), 6.87(dt, 1H), 6.97(dt, 1H), 7.01(dd, 1H), 7.19- 7.14(m, 2H),7.30-7.25(m, 2H); MS(APCI)m/z(rel intensity) 423.4(100). 63% yield. 86CH₂(2-Cl)Ph ¹H NMR(CDCl₃): δ2.24(s, 3H), 2.65-3.14(m, 7H), 3.99-4.05(m,2H), 4.96(s, 1H), 6.20(s, 1H), 6.59(d, 1H), 6.87(t, 1H), 6.97(t, 1H),7.02(d, 1H), 7.18-7.22(m, 2H), 7.27(m, 1H), 7.39(m, 1H); MS(APCI)m/z(relintensity)423(100), 425(39). 200 mg of product. 87 CH₂(3-Cl)Ph ¹HNMR(CDCl₃): δ2.28(s, 3H), 2.58-3.04(m, 5H), 3.98(m, 1H), 4.08(m, 1H),4.96(s, 1H), 6.21(s, 1H), 6.61(d, 1H), 6.88(t, 1H), 6.98(t, 1H), 7.03(d,1H), 7.11(m, 1H), 7.21-7.28(m, 3H); MS(APCI)m/z(rel intensity)423(100),425(39). 88 CH₂(3,5-Di-F)Ph ¹H NMR(CDCl₃): δ2.27(s, 3H), 2.58-2.70(m,2H), 2.77(dd, 1H), 2.83-3.06(m, 4H), 3.95(m, 1H), 4.07(m, 1H), 4.99(s,1H), 6.21(s, 1H), 6.60(d, 1H), 6.69(t, 1H), 6.76-6.83(m, 2H), 6.87(t,1H), 6.96(t, 1H), 7.01(d, 1H); MS(APCI)m/z(rel intensity)425(100). 10 mgof product. 89 CH₂(3-CF₃)Ph mp 105-117° C.: ¹H NMR(CDCl₃): δ2.24(s, 3H),2.68-2.73(m, 2H), 2.82-2.89(m, 2H), 2.95-3.10(m, 3H), 3.98(m, 1H),4.11(m, 1H), 5.00(s, 1H), 6.19(s, 1H), 6.60(d, 1H), 6.88(t, 1H), 6.96(t,1H), 7.01(d, 1H), 7.42-7.50(m, 4H); MS(APCI) m/z(rel intensity)457(100).

Example 902-Methyl-10-(4-methyl-3-(S)-phenethyl-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene

Add aqueous 37% formaldehyde (45 mL, 0.55 mmol) to a solution of2-methyl-10-(3-(S)-phenethyl-piperazin-1-yl)-4H-3-thia-4,9-diazabenzo[f]azulene(200 mg, 0.5 mmol) in dichloroethane (30 mL). Stir the mixture 2 minutesand add sodium triacetoxyborohydride (159 mg, 0.75 mmol). Stir thesuspension for 30 minutes and quench with a saturated aqueous solutionof sodium bicarbonate. Extract the aqueous phase 3 times withdichloromethane and combine the organic phases, dry (MgSO₄), filter andconcentrate. Purify the residue via chromatography eluting withmethylene chloride/methanol (90:10) to provide the title compound as ayellow solid (143 mg, 67%): mp 87-91° C.: ¹H NMR (CDCl₃): δ1.78 (m, 1H),1.96 (m, 1H), 2.22 (m, 1H), 2.32 (s, 3H), 2.35 (s, 3H), 2.38 (ddd, 1H),2.58 (ddd, 1H), 2.75 (ddd, 1H), 2.86 (ddd, 1H), 2.94 (dd, 1H), 3.16(ddd, 1H), 3.90 (m, 1H), 4.05 (m, 1H), 4.94 (s, 1H), 6.30 (s, 1H), 6.60(d, 1H), 6.87 (t, 1H), 6.98 (t, 1H), 7.04 (d, 1H), 7.17-7.32 (m, 5H); MS(APCI) m/z (rel intensity) 417 (100).

Example 91(S)-2-Methyl-10-(4-methyl-3-phenethyl-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulenedihydrochloride

Dissolve(S)-2-methyl-10-(4-methyl-3-phenethyl-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulenein ethyl acetate add hydrochloride acid until the title compoundprecipates as the dihydrochloride salt as a yellow solid: mp 225° C.;mass spectrum (ion spray): m/z=417 (M+1); Analysis for C₂₅H₃₀Cl₂N₄S(0.3H₂O): calcd: C, 60.67; H, 6.23; N. 11.32; found: C, 60.76; H, 6.17; N,11.13.

By method similar Example 90, using the appropriate starting materials,the following compounds were prepared and isolated as the free base andas the (S) isomer except where noted:

No: ArAlk Data 92 CH₂Ph mp 94-97° C.; ¹H NMR(CDCl₃): δ2.12(s, 3H),2.36-2.48(m, 3H), 2.49(s, 3H), 2.79(ddd, 1H), 2.92(ddd, 1H),3.12-3.23(m, 2H), 3.58(m, 1H), 3.94(m, 1H), 4.90(s, 1H), 5.96(s, 1H),6.57(d, 1H), 6.82-6.86(m, 1H), 6.91-6.96(m, 1H), 7.14-7.29(m, 5H);MS(APCI)m/z(rel intensity)403(100), 346(80). 93% yield. 93CH₂(4-O—CH₂CH═CH₂)Ph mp 97-108° C.; ¹H NMR(CDCl₃)δ2.12(s, 3H),2.39-2.32(m, 2H), 2.43(dd, 1H), 2.48(s, 3H), 2.78(m, 1H), 2.90(dt, 1H),3.09(d, 1H), 3.21(m, 1H), 3.60(d, 1H), 3.97(d, 1H), 4.49(dt, 2H),4.94(bs, 1H), 5.30-5.25(m, 1H), 5.43-5.36(m, 1H), 5.96(s, 1H),6.10-5.98(m, 1H), 6.56(dd, 1H), 6.86-6.78(m, 3H), 6.95-6.91(m, 2H),7.05(d, 1H); MS(APCI)m/z(rel intensity) 459.4(39), 665.5(100). 71%yield. 94 CH₂(pyridin-2-yl) mp 94-102° C.; ¹H NMR(CDCl₃)δ2.18(s, 3H),2.44(dd, 1H), 2.49(s, 3H), 2.70(dd, 1H), 2.76(dt, 1H), 2.95-2.84(m, 2H),3.23(ddd, 1H), 3.30(dd, 1H), 3.58(d, 1H), 3.93(d, 1H), 4.95(bs, 1H),6.08(s, 1H), 6.57(dd, 1H), 6.84(ddd, 1H), 6.98-6.89(m, 2H), 7.19-7.09(m,2H), 7.57(dt, 1H), 8.55(m, 1H); MS (APCI)m/z(rel intensity)311.3(100),404.3(74). 82% yield. 95 (R)CH₂Ph mp 64-82° C.: ¹H NMR(CDCl₃)δ2.12(s,3H), 2.36-2.48(m, 3H), 2.49(s, 3H), 2.79(ddd, 1H), 2.92(ddd, 1H),3.12-3.23(m, 2H), 3.58(m, 1H), 3.94(m, 1H), 4.90(s, 1H), 5.96(s, 1H),6.57(d, 1H), 6.82-6.86(m, 1H), 6.91-6.96(m, 2H), 7.14-7.29(m, 5H);MS(APCI)m/z(rel intensity)403(100), 346(80). 87% yield. 89% yield. 100CH₂(naphthalen-2-yl) mp 89-102° C.; ¹H NMR(CDCl₃): δ1.70(bs, 3H),2.43(m, 1H), 2.50(m, 1H), 2.52(s, 3H), 2.59(m, 1H), 2.86(m, 1H), 2.93(m,1H), 3.22(m, 1H), 3.34(dd, 1H), 3.62(m, 1H), 4.02(m, 1H), 4.86(s, 1H),5.83(s, 1H), 6.55(d, 1H), 6.80-6.92(m, 3H), 7.30(d, 1H), 7.44(m, 2H),7.60(s, 1H), 7.73-7.83(m, 3H); MS (APCI)m/z(rel intensity)453(100). 71%yield. 101 CH₂(naphthalen-1-yl) mp 98-116° C.; ¹H NMR(CDCl₃): δ1.87(bs,3H), 2.47(m, 1H), 2.64(m, 1H), 2.65(s, 3H), 2.80-2.94(m, 2H), 3.00(m,1H), 3.23(m, 1H), 3.43(m, 1H), 3.77(dd, 1H), 3.97(m, 1H), 4.92(s, 1H),5.72(bs, 1H), 6.53(d, 1H), 6.80-6.92(m, 3H), 7.28-7.36(m, 2H),7.45-7.55(m, 2H), 7.71(d, 1H), 7.86(d, 1H), 8.07(d, 1H); MS(APCI)m/z(relintensity)453(100). 58% yield. 102 CH₂(4-CH₃)Ph mp 81-93° C.; ¹HNMR(CDCl₃): δ2.12(s, 3H), 2.31(s, 3H), 2.45-2.35(m, 3H), 2.49(s, 3H),2.82-2.72(m, 1H), 2.92(dt, 1H), 3.23-3.09(m, 2H), 3.61(d, 1H), 4.00(bd,1H), 4.90(s, 1H), 5.96(bs, 1H), 6.58-6.55(m, 1H), 6.85(ddd, 1H),6.96-6.92(m, 2H), 7.09-7.02(m, 4H); MS(APCI)m/z(rel intensity)417.4(100). 73% yield 103 CH₂(3-CH₃)Ph mp 67-83° C.; ¹H NMR(CDCl₃): δ2.31(s,3H), 2.40(s, 3H), 2.47-2.36(m, 3H), 2.49(s, 3H), 2.86-2.76(m, 1H),2.91(dt, 1H), 3.25-3.06(m, 2H), 3.61(d, 1H), 3.99-3.88(m, 1H)4.89(s,1H), 5.97(s, 1H), 6.57(d, 1H), 6.88-6.81(m, 1H), 7.02-6.96(m, 5H),7.19-7.10(m, 1H); MS(APCI)m/z(rel intensity)417.3 (100). 74% yield. 104CH₂(2-F)Ph mp 69-81° C.; ¹H NMR(CDCl₃): δ2.14(s, 3H), 2.52(s, 3H),2.53-2.38(m, 3H), 2.95-2.82(m, 2H), 3.26-3.17(m, 2H), 3.58(d, 1H),3.95(d, 1H), 4.90(s, 1H), 6.03(s, 1H), 6.58-6.54(m, 1H), 6.87-6.82(m,1H), 7.05-6.90(m, 4H), 7.21-7.14(m, 2H); MS(APCI)m/z(relintensity)421.3(100). 94% yield. 105 CH₂(3-F)Ph mp 74-88° C.; ¹HNMR(CDCl₃): δ2.16(s, 3H), 2.48(s, 3H), 2.52-2.39(m, 3H), 2.82(dd, 1H),2.91(dt, 1H), 3.17-3.14(m, 1H), 3.26-3.18(m, 1H), 3.57(d, 1H), 3.95(d,1H), 4.19(s, 1H), 6.02(s, 1H), 6.58-6.55(m, 1H), 6.98-6.82(m, 6H),7.26-7.18(m, 1H); MS(APCI)m/z(rel intensity)421.3(100). 81% yield. 106CH₂(4-F)Ph mp 76-84° C.; ¹H NMR(CDCl₃): δ2.08(s, 3H), 2.43(s, 3H),2.45-2.23(m, 3H), 2.76-2.65(m, 1H), 2.86(dt, 1H), 3.07(d, 1H),3.22-3.07(m, 1H), 3.52(bd, 1H), 3.90(bd, 1H), 5.05-4.79(m, 1H), 5.90(s,1H), 6.50(d, 1H), 6.81-6.75(m, 1H), 6.92-6.83(m, 4H), 7.08-7.02(m, 2H);MS(APCI)m/z(rel intensity)421.4 (100). 81% yield. 107 CH₂(3-CF₃)Ph mp88-105° C.; ¹H NMR(CDCl₃): δ2.11(s, 3H), 2.51(s, 3H), 2.60-2.38(m, 3H),2.96-2.78(m, 2H), 3.30-3.16(m, 2H), 3.59(bd, 1H), 3.92(bd, 1H), 4.92(s,1H), 5.99(s, 1H), 6.57(d, 1H), 6.96-6.82(m, 3H), 7.50-7.36(m, 4H);MS(APCI)m/z(rel intensity)471.3(100). 57% yield. 108 CH₂(2-CF₃)Ph ¹HNMR(CDCl₃): δ2.14(s, 3H), 2.46(m, 2H), 2.50(s, 3H), 2.62(m, 1H), 2.70(m,1H), 2.90-2.97(m, 2H), 3.24(m, 1H), 3.42(dd, 1H), 3.46(dd, 1H), 4.93(s,1H), 6.04(s, 1H), 6.57(d, 1H), 6.86(t, 1H), 6.90-6.97(m, 2H),7.26-7.40(m, 2H), 7.43(t, 1H), 7.64(d, 1H); MS(APCI)m/z(relintensity)471(100). 58% yield. 109 CH₂(2-OCH₃)Ph mp 81-93° C.; ¹HNMR(CDCl₃): δ2.12(s, 3H), 2.49(m, 3H), 2.51(s, 3H), 2.90-2.83(m, 1H),2.92(dt, 1H), 3.25-3.16(m, 2H), 3.57(d, 1H), 3.79(s, 3H), 3.96(bd, 1H),4.89(s, 1H), 5.98(bs, 1H); 6.56(dd, 1H), 6.87-6.81(m, 3H), 6.95-6.91(m,2H), 7.08(d, 1H), 7.19(dt, 1H); MS(APCI)m/z(rel intensity)433.4 (100).73% yield. 110 CH₂(3-OCH₃)Ph mp 70-82° C.; ¹H NMR(CDCl₃): δ2.13(s, 3H),2.48-2.37(m, 3H), 2.49(s, 3H), 2.79(dd, 1H), 2.91(dt, 1H), 3.23-3.11(m,2H), 3.62(d, 1H), 3.77(s, 3H), 3.98(d, 1H), 4.90(bs, 1H), 5.99(s, 1H),6.57(d, 1H), 6.77-6.69(m, 3H), 6.85(ddd, 1H), 6.95- 6.92(m, 2H), 7.18(t,1H); MS(APCI)m/z(rel intensity)433.3 (100). 68% yield. 111 CH₂(4-OCH₃)Phmp 74-88° C.; ¹H NMR(CDCl₃): δ2.10(s, 3H), 2.44-2.29(m, 3H), 2.46(s,3H), 2.74(dd, 1H), 2.89(dt, 1H), 3.08(d, 1H), 3.16(ddd, 1H), 3.58(d,1H), 3.76(s, 3H), 3.97(d, 1H), 4.90(bs, 1H), 5.94(s, 1H), 6.54(d, 1H),6.84-6.76(m, 3H), 6.93-6.89(m, 2H), 7.06-7.02(m, 2H); MS(APCI)m/z(relintensity)433.3(50), 242.5(100). 74% yield. 112 CH₂(3,4-di-Cl)Ph mp87-94° C.; ¹H NMR(CDCl₃): δ2.17(s, 3H), 2.38-2.50(m, 3H), 2.47(s, 3H),2.82-2.93(m, 2H), 3.08(ddd, 1H), 3.24(ddd, 1H), 3.57(d, 1H), 3.91(m,1H), 4.92(s, 1H), 6.01(s, 1H), 6.57(d, 1H), 6.86(m, 1H), 6.92-6.97(m,2H), 7.01(dd, 1H), 7.27(d, 1H), 7.32(d, 1H); MS(APCI)m/z(relintensity)471(100), 473 (62). 54% yield. 113 CH₂(indol-3-yl) mp 138-156°C.; ¹H NMR(CDCl₃): δ1.90(s, 3H), 2.43(dt, 1H), 2.55(s, 3H), 2.67-2.51(m,2H), 2.90-2.78(m, 1H), 2.94(bd, 1H), 3.31-3.17(m, 2H), 3.74(bd, 1H),3.98(bd, 1H), 4.94(bs, 1H), 5.87(s, 1H), 6.51(d, 1H), 6.83-6.77(m, 1H),6.93-6.88(m, 2H), 6.96(s, 1H), 7.10(dt, 1H), 7.16(dt, 1H), 7.31(d, 1H),7.59(d, 1H), 8.18(bs, 1H); MS(APCI)m/z(rel intensity)442.4 (100). 63%yield. 114 CH₂(thiophen-2-yl) mp 85-87° C.; ¹H NMR(CDCl₃): δ2.20(s, 3H),2.39-2.48(m, 2H), 2.47(s, 3H), 2.79-2.85(m, 2H), 2.90(ddd, 1H),3.18(ddd, 1H), 3.27(dd, 1H), 3.73(m, 1H), 3.97(m, 1H), 4.91(s, 1H),6.11(s, 1H), 6.57(d, 1H), 6.79-7.00(m, 5H), 7.13(d, 1H); MS(APCI)m/z(rel intensity)409(100). 53% yield. 115CH₂(benzo(b)thiophen-3-yl) mp 84-97° C.; ¹ H NMR(CDCl₃): δ1.99(s, 3H),2.46(dt, 1H), 2.56(s, 3H), 2.70-2.62(m, 1H), 2.76(dd, 1H), 2.97-2.85(m,2H), 3.26(t, 1H), 3.34(dd, 1H), 3.67(d, 1H), 3.94(d, 1H), 4.88(bs, 1H),5.88(s, 1H), 6.53(d, 1H), 6.85-6.79(m, 1H), 6.94-6.88(m, 2H), 7.16(s,1H), 7.33(dd, 1H), 7.37(dd, 1H), 7.74(d, 1H), 7.83(d, 1H);MS(APCI)m/z(rel intensity)459.3(100). 82% yield. 118 CH₂(2-Cl)Ph ¹HNMR(CDCl₃): δ2.14(s, 3H), 2.34-2.67(m, 3H), 2.54(s, 3H), 2.91-2.96(m,2H), 3.22(ddd, 1H), 3.38(m, 1H), 3.52(m, 1H), 3.93(m, 1H), 4.92(s, 1H),6.04(s, 1H), 6.56(d, 1H), 6.86(t, 1H), 6.92-6.97(m, 2H), 7.12-7.19(m,3H), 7.36(m, 1H); MS (APCI)m/z(rel intensity)437(100), 439(39). 119CH₂(3-Cl)Ph ¹H NMR(CDCl₃): δ2.16(s, 3H), 2.42-2.48(m, 3H), 2.49(s, 3H),2.83(m, 1H), 2.90(m, 1H), 3.13(dd, 1H), 3.24(ddd, 1H), 3.57(ddd, 1H),3.93(m, 1H), 4.92(s, 1H), 6.01(s, 1H), 6.57(d, 1H), 6.85(m, 1H),6.93-6.96(m, 2H), 7.05(m, 1H), 7.16-7.20(m, 3H); MS(APCI)m/z(relintensity)437(100), 439(44). 120 CH₂(4-Cl)Ph mp 64-77° C.: ¹HNMR(CDCl₃): δ2.16(s, 3H), 2.48(s, 3H), 2.51-2.33(m, 3H), 2.78(dd, 1H),2.90(dt, (1H), 3.19(ddd, 1H), 3.57(d, 1H), 3.97(bd(1H), 4.91(bs, 1H),5.96(d, 1H), 6.57(dd, 1H), 6.85(ddd, 1H), 6.96-6.91(m, 2H), 7.12-7.07(m,2H), 7.27- 7.21(m, 2H); MS(APCI)m/z(rel intensity)437(100), 439(44). 121CH₂(4-OPh)Ph mp 94-101° C.; ¹H NMR(CDCl₃)δ2.17(s, 3H), 2.48-2.38(m, 2H),2.49(s, 3H), 2.81(m, 1H), 2.92(dt, 1H), 3.14(d, 1H), 3.23(t, 1H),3.61(d, 1H), 3.94(d, 1H), 5.10-4.91(m, 1H), 6.08(bs, 1H), 6.56(d, 1H),6.83(ddd, 1H), 6.98-6.88(m, 6H), 7.14-7.05(m, 4H), 7.35-7.29(m, 2H);MS(APCI)m/z(rel intensity)495.7 (100). 80% yield. 122 CH₂(3-OPh)Ph mp.89-93° C.: ¹H NMR(CDCl₃)δ2.14(s, 3H), 2.50-2.40(m, 3H), 2.47(s, 3H),2.80(bs, 1H), 2.93(d, 1H), 3.14(d, 1H), 3.28(bs, 1H), 3.60(d, 1H),3.96(d, 1H), 4.90(s, 1H), 5.97(s, 1H), 6.56(dd, 1H), 6.90-6.82(m, 3H),7.01-6.91(m, 5H), 7.09(ddd, 1H), 7.24(t, 1H), 7.36-7.30(m, 2H);MS(APCI)m/z(rel intensity)495.4(100). 94% yield. 123 CH₂(3-O-i-Pr)Ph ¹HNMR(CDCl₃)δ1.29(dd, 6H), 2.14(s, 3H), 2.40(m, 3H), 2.48(s, 3H), 2.80(m,1H), 2.90(dt, 1H), 3.15(m, 2H), 3.61(d, 1H), 3.98(m, 1H), 4.51(m, 1H),4.89(s, 1H), 5.98(s, 1H), 6.57(d, 1H), 6.72(m, 3H), 6.84(m, 1H), 6.93(d,12H), 7.16(t, 1H); MS(ESI)m/z(rel intensity)461(100). Product isolatedas a yellow solid 124 CH₂(2,4-di-OCH₃)Ph ¹H NMR(CDCl₃)δ2.12(s, 3H),2.31-2.47(m, 3H), 2.49(s, 3H), 2.82(m, 1H), 2.91(ddd, 1H), 3.11(dd, 1H),3.19(ddd, 1H), 3.58(m, 1H), 3.75(s, 3H), 3.78(s, 3H), 3.97(m, 1H),4.94(s, 1H), 5.97(s, 1H), 6.36-6.45(m, 2H), 6.56(d, 1H), 6.83(m, 1H),6.91-6.97(m, 3H); MS(APCI)m/z(rel intensity)463(100). Product isolatedas a yellow solid.

Example 125 2-Methyl-4H-3-thia-4,9-diazabenzo[f]azulen-10-ylamine

Dissolve 2-methyl-4H-3-thia-4,9-diazabenzo[f]azulen-10-ylaminehydrochloride (6 g, 22.6 mmoles) in a 5:1 mixture of dichloromethane andcommercial 7N ammonia-methanol, wash with half a volume of SN aqueoussodium hydroxide. Separate the organic layer and extract the aqueouslayer twice with dichloromethane. Combine all organic extracts, dry overmagnesium sulfate, filter and concentrate in vacuo to yield the titlefree base as an orange solid: ¹H NMR (DMSO-d₆): δ8.10-7.80 (br, 1H),7.30-6.90 (br, 2H), 6.80-6.65 (m, 3H), 6.59 (br dd, 1H, J=7.6, 1.6 Hz),6.52 (br s, 1H), 2.22 (br s, 3H).

Example 126 2-Methyl-4H-3-thia-4,9-diaza-benzo[f]azulene-10-ylamine

Slurry 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene-10-ylaminehydrochloride (5.2 g, 19.5 mmol) in water and add 1N sodium hydroxide(19.5 mL, 19.5 mmol). Add methanol to facilitate stirring and extractwith methylene chloride. Purify the methylene chloride extracts bysilica gel chromatography using 7N ammonia in methanol-methylenechloride (5%) as the eluent to give (4.13 g, 92%) of the title compound.

Example 127 and Example 127a (S)-1,4-Dibenzyl-2-vinylpiperazine(R)-1,4-Dibenzyl-2-vinylpiperazine

Add anhydrous tetrahydrofuran (4.5 L) to a 10 L flange-neck flaskequipped with an air stirrer rod and paddle, thermometer, and nitrogeninlet and outlet tubes. Purge with dry nitrogen gas (inlet tube had asintered end for maximum gas dispersal) the body of the liquid for 1 h,add tris(dibenzylideneacetone)dipalladium(0) chloroform adduct (36.0 g,34.8 mmol). Add isopropyl phosphite (67.8 mL, 0.275 mol) in one lot tothe mixture still under nitrogen and stir. After 5 minutes, the colorlightens from purple to amber. Add dibenzylethylenediamine (322.0 g,1.34 mol) in one lot, followed by the dropwise addition ofcis-1,4-diacetoxy-2-butene (214 mL, 1.34 mol) over 15 minutes stir undernitrogen for 18 hours. Remove the solvent in vacuo at 40° C. anddissolve the residual oil in diethyl ether (2.5 L) and extract with 1Naq. sodium hydroxide (2×2 L). Wash the bulked aqueous extracts withdiethyl ether (2×) and basify to pH 14 using 5N aq. sodium hydroxide andextract with diethyl ether (3×). Dry the buIlked ethereal extracts overmagnesium sulphate, filter and evaporate to dryness in vacuo at 40° C.Purification by chromatography on silica (117 kg) using 1%methanol/ether (can also use dichloromethane) gives a pale yellow oil(377.35 g, 96%) 1H NMR and Mass Spec are consistent with product.

Dissolve the mixture of isomers in ethyl acetate (3670 mL) and addportionwise to a hot solution of (S)-(+)-mandelic acid (385 g, 2 eq.) inethyl acetate (3850 mL), starting at 72° C. Chill the mixture to 0° C.and seed with crystals (which were previously obtained from an earlierresolution). Place the mixture in the freezer (−20° C.) overnight.Scrape the crystalline solid away from the sides of the flask and allowthe mixture to warm to 0° C. Isolate the solid dry. Further dry thematerial in vacuo at room temperature. Yield=252.6 g, white, crystallinesolid of the S-mandelic acid salt of the(R)-1,4-dibenzyl-2-vinylpiperazine.

Evaporate the filtrate to dryness in vacuo at 40° C. to leave an amberoil. Dissolve the filtrate in dichloromethane (2 L) and wash thesolution with 1N aq. sodium hydroxide (2 L+1 L), brine (1 L) and dryover magnesium sulphate. Filter and evaporate to dryness in vacuo at 45°C. to yield the recovered free base. Further dry by vacuum. Extract theaqueous liquors with dichloromethane to further recover any remainingfree base (207.6 g). Chiral HPLC showed the material to consist of a85:15 ratio of isomers in favour of the required isomer.

Add (R)-(−)-mandelic acid (216 g, 1.42 mol) and ethyl acetate (2.5 L) toa 10 liter flange-neck flask equipped with an air stirrer rod andpaddle, thermometer and water condenser and warm the suspension to 60°C. Add a solution of free base (207.6 g, 0.71 mol) in ethyl acetate (500mL) and allow to cool down to room temperature and place in the freezerovernight (at 35° C. solid starts to precipitate). Isolate thecrystalline solid by filtration and pull dry. Further dry in vacuo atroom temperature(290.34 g).

Recrystallize from hot ethyl acetate (2.3 L) at 70° C. Allow thissolution to cool down to room temperature overnight after seeding.Filtration and drying in vacuo at room temperature gives the R-mandelicacid salt of the (S)-1,4dibenzyl-2-vinylpiperazine from which the freebase may be prepared (225.44 g). Chiral HPLC showed: 98.74%+1.26%: ¹HNMR, OMSO d₆): δ7.20-7.35 (m, 10H); 5.75-5.90 (m, 1H); 5.15-5.30 (q,2H); 3.85-3.95 (d, 1H); 3.40-3.45 (s, 2H); 3.00-3.10 (d, 1H); 2.80-2.90(t, 1H); 2.55-2.60 (d, 3H); 1.95-2.10 (m, 311).

Example 128 (S)-1,4-Dibenzyl-2-(2-pyridin-2-yl-ethyl)-piperazine

Combine 9-borabicyclo[3.3.1]nonane (62.6 mL, 31.3 mmol, 0.5 M in THF)and (S)-1,4-dibenzyl-2-vinyl-piperazine. (2.29 g, 7.83 mmol) and stir atambient temperature. After 18 hours, add triphenylphosphine (657 mg,2.50 mmol), tetrakis(triphenylphosphine) palladium(0) (362 mg, 0.31mmol), and 2-bromopyridine (1.12 mL, 11.7 mmol). Add 3M NaOH (6.4 mL,19.3 mmol) slowly, and gas evolution will occur. Heat at reflux. After24 hours, cool to ambient temperature, add 5N HCl (50 mL), and stir 1hour. Dilute with 0.2 N HCl, extract with diethyl ether, and discard thediethyl ether extracts. Add 5N NaOH to the acidic aqueous solution untilpH is 12-14. Extract with diethyl ether. Wash the diethyl ether extractswith water and brine, dry over sodium sulfate, filter and concentrateunder reduced pressure. Purify by silica gel chromatography using 2Nammonia in methanol-methylene chloride (0.5%-3%) as the eluent to givethe title compound (2.3 g, 79%): mp 83-86° C.; mass spectrum (ionspray): m/z=372 (M+1). Analysis calculated for C₂₅H₂₉N₃: C, 80.82; H,7.87; N, 11.31. Found: C, 80.56; H, 7.60; N, 11.30.

Example 129 (S)-1,4-Dibenzyl-2-(2-pridin-4-yl-ethyl)-piperazine

Prepared by the method in Example 128, using 9-borabicyclo[3.3.1]nonane(71.4 mL, 35.7 mmol, 0.5 M in THF), (S)-1,4-dibenzyl-2-vinyl-piperazine(2.61 g, 8.92 mmol), triphenylphosphine (749 mg, 2.86 mmol),tetrakis(triphenylphosphine)palladium(0) (413 mg, 0.36 mmol),4-bromopyridine hydrochloride (2.60 g, 13.4 mmol) and 3M NaOH (10.4 mL,31.2 mmol) to give the title compound (1.87 g, 56%): mp 96-98° C.; massspectrum (ion spray): m/z=372 (M+1). Analysis calculated for C₂₅H₂₉N₃:C, 80.82; H, 7.87; N, 11.31. Found: C, 80.80; H, 7.99; N, 11.18.

Example 130 (S)-2-(2-Pyridin-2-yl-ethyl)-piperazine

Dissolve (S)-1,4-dibenzyl-2-(2-pyridin-2-yl-ethyl)-piperazine (2.86 g,7.69 mmol) in ethanol (50 mL). Add ammonium formate (2.43 g, 38.5 mmol)and palladium (430 mg, 5 wt. % on carbon) and heat to reflux. After 6hours 40 minutes, filter the palladium on carbon and concentrate thefiltrate. Purify by silica gel chromatography using 7N ammonia inmethanol-methylene chloride (5%-15%) as the eluent to give the titlecompound (1.1 g, 75%): mp 83-87° C.; mass spectrum (ion spray): m/z=192(M+1). Analysis calculated for C₁₁H₁₇N₃: C, 69.07; H, 8.96; N, 21.97.Found: C, 68.84; H, 8.85; N, 21.65.

Example 131 (S)-2-(2-Pyridin-4-yl-ethyl)-piperazine

Dissolve (S)-1,4-dibenzyl-2-(2-pyridinyl-ethyl)-piperazine (2.14 g, 5.76mmol) in ethanol (40 mL). Add ammonium formate (2.18 g, 34.6 mmol) andpalladium (430 mg, 5 wt. % on carbon) and heat to reflux. After 6 hours30 minutes, filter the palladium on carbon and concentrate the filtrate.Purify by silica gel chromatography using 7N ammonia inmethanol-methylene chloride (5%-15%) as the eluent to give 945 mg (86%)of the title compound: mp 113-116° C.; mass spectrum (ion spray):m/z=192 (M+1). Analysis calculated for C₁₁H₁₇N₃: C, 69.07; H, 8.96; N,21.97. Found: C, 69.08; H, 8.77; N, 21.81.

Example 132(S)-2-Methyl-10-(3-(2-pyridin-2-yl-ethyl)-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulenetrihydrochloride

Combine (S)-2-(2-pyridin-2-yl-ethyl)-piperazine (470 mg, 2.46 mmol),2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine (282 mg, 1.23mmol), toluene (8 mL), and DMSO (2 mL). Heat at 110° C. After 41 hours,cool to ambient temperature and dilute with ethyl acetate and water.Extract with ethyl acetate. Wash the extracts with water and brine, dryover sodium sulfate, filter and concentrate the filtrate. Purify bysilica gel chromatography using 7N ammonia in methanol-methylenechloride (2.5%) as the eluent to give 270 mg. Purify again by silica gelchromatography using 2N ammonia in methanol-methylene chloride (2%-5%)as the eluent to give the free base. Crystallize as the trihydrochloridesalt from ethyl acetate and ethanol to give the title compound (20 g,40%): mp 220-224° C. dec.; mass spectrum (ion spray): m/z=404 (M+1).Analysis calculated for C₂₃H₂₅N₅S.2.7HCl: C, 55.03; H, 5.56; N, 13.95.Found: C, 55.22; H, 5.59; N, 13.81.

Example 133(S)-2-Methyl-10-(3-(2-pyridin-4-yl-ethyl)-piperazin-1-yl)-4H-3-thia-49-diaza-benzo[f]azulenetrihydrochloride

Combine (S)-2-(2-pyridin-4-yl-ethyl)-piperazine (889 mg, 4.65 mmol),2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine (533 mg, 2.32mmol), toluene (12 mL), and DMSO (3 mL). Heat at 110° C. After 72 hours,cool to ambient temperature and dilute with ethyl acetate and water.Extract with ethyl acetate. Wash the extracts with water and brine, dryover sodium sulfate, filter and concentrate the filtrate. Purify bysilica gel chromatography using 2N ammonia in methanol-methylenechloride (2%-4%) as the eluent to give the free base. Crystallize as thetrihydrochloride salt from ethyl acetate and ethanol to give the titlecompound (486 mg, 52%): mp 234-239° C. dec.; mass spectrum (ion spray):m/z=404 (M+1). Analysis calculated for C₂₃H₂₅N₅S.3HCl: C, 53.86; H,5.50; N, 13.65. Found: C, 53.71; H, 5.79; N, 13.37.

Example 134 (S)-1,4-Dibenzyl-2-(2-(4-fluoro-phenyl-ethyl)-piperazine

Combine (s)-1,4-dibenzyl-2-vinyl-piperazine (2.0 g, 6.84 mmol) and9-borabicyclo[3.3.1]nonane (82.1 mL, 41.04 mmol, 0.5 M in THF) and stirat ambient temperature. After 6 hours 30 minutes, add1-fluoro-4-iodo-benzene (2.3 g, 10.26 mmol), triphenylphosphine (287.0mg, 1.09 mmol), tetrakis(triphenylphosphine) palladium(0)(158.0 mg, 0.14mmol), and 3N NaOH (5.6 ml) and stir at 60° C. After 22 hours, addethanolamine (10.0 mL) and dilute the mixture with water. Extract withethyl acetate and combine, wash (brine), dry (sodium sulfate), andreduce the extracts to residue. Purify the residue on silica gel usingethyl acetate/hexanes (5:95) to give a yellow oil. Dissolve the yellowoil in acetic acid/methanol (1:9) and apply to an SCX column. Wash thecolumn with methanol followed by 2N ammonia in methanol to give thetitle compound: mp 79-82° C.; mass spectrum (ion spray): m/z=389.4(M+1).

Example 135 (S)-1,4-Dibenzyl-2-(2-(3-fluoro-phenyl)-ethyl)-piperazine

Combine (S)-1,4-dibenzyl-2-yinyl-piperazine (2.0 g, 6.84 mmol) and9-borabicyclo[3.3.1]nonane (82.1 mL, 41.04 mmol, 0.5 M in THF) and stirat ambient temperature. After 24 hours, add 1-fluoro-3-iodo-benzene (2.3g, 10.26 mmol), triphenylphosphine (287.0 mg, 1.09 mmol),tetrakis(triphenylphosphine) palladium(0)(158.0 mg, 0.14 mmol), and 3NNaOH (5.6 mL) and stir at 60° C. After 22 hours, add ethanolamine (10.0mL) and dilute the mixture with water. Extract with ethyl acetate andcombine, wash (brine), dry (sodium. sulfate), and reduce the extracts toresidue. Purify the residue on silica gel using ethyl acetate/hexanes(5:95) to give a yellow oil. Dissolve the yellow oil in aceticacid/methanol (1:9) and apply to an SCX column. Wash the column withmethanol followed by 2N ammonia in methanol to give the title compound:mp 69-71° C.; mass spectrum (ion spray): m/z=389.4 (M+1).

Example 136 (S)-1,4-Dibenyl-2-(2-(2-fluoro-phenyl)-ethyl)-piperazine

Combine (S)-1,4-dibenzyl-2-vinyl-piperazine (2.0 g, 6.84 mmol) and9-borabicyclo[3.3.1]nonane (82.1 mL, 41.04 mmol, 0.5 M in THF) and stirat ambient temperature. After 24 hours, add 1-fluoro-2-iodo-benzene (2.3g, 10.26 mmol), triphenylphosphine (287.0 mg, 1.09 mmol),tetrakis(triphenylphosphine) palladium(0)(158.0 mg, 0.14 mmol), and 3NNaOH (5.6 mL) and stir at 60° C. After 22 hours, add ethanolamine (10.0mL) and dilute the mixture with water. Extract with ethyl acetate andcombine, wash (brine), dry (sodium sulfate), and reduce the extracts toresidue Purify the residue on silica gel using ethyl acetate/hexanes(5:95) to give a yellow oil. Dissolve the yellow oil in aceticacid/methanol (1:9) and apply to an SCX column. Wash the column withmethanol followed by 2N ammonia in methanol to give the title compound:mp 62-66° C.; mass spectrum (ion spray): m/z=389.4 (M+1).

Example 137 (S)-2-(2-(4-Fluoro-phenyl)-ethyl)-piperazine

Combine (S)-1,4-dibenzyl-2-(2-(4-fluoro-phenyl)-ethyl)-piperazine (1.94g, 4.99 mmol), ammonium formate (1.57 g, 24.95 mmol), 5% Pd/C (241.1mg), and ethanol (50 mL) and stir and heat the mixture at reflux. After4 hours 30 minutes, cool to ambient temperature and remove the catalystby vacuum filtration through celite. Reduce the filtrate to residue anddissolve it in 1N NaOH. Extract with dichloromethane and combine, wash(brine), dry (sodium sulfate), and reduce the extracts to residue.Purify the residue on silica gel using dichloromethane/2N ammonia inmethanol (80:20) to give the title compound as a white solid: mp112-114° C.; mass spectrum (ion spray): m/z=209.3 (M+1); Analysis forC₁₂H₁₇FN₂: calcd: C, 69.20; H, 8.23; N, 13.45; found: C, 68.97; H, 8.14;N, 13.21.

Example 138 (S)-2-(2-(3-Fluoro-phenyl)-ethyl)-piperazine

Combine (S)-1,4-dibenzyl-2-(2-(3-fluoro-phenyl)-ethyl)-piperazine (1.96g, 5.04 mmol), ammonium formate (1.59 g, 25.18 mmol), 5% Pd/C (243.3mg), and ethanol (50 mL). Stir and heat the mixture at reflux. After 4hours 30 minutes, cool to ambient temperature and remove the catalyst byvacuum filtration through celite. Reduce the filtrate to residue andpurify it on silica gel using dichloromethane/2N ammonia in methanol(80:20) to give the title compound as a white solid: mp 95-99° C.; massspectrum (ion spray): m/z=209.3 (M+1); Analysis for C₁₂H₁₇FN₂: calcd: C,69.20; H, 8.23; N, 13.45; found: C, 69.13; H, 8.40; N, 13.28.

Example 139 (S)-2-(2-(2-Fluoro-phenyl)-ethyl)-piperazine

Combine (S)-1,4-dibenzyl-2-(2-(2-fluoro-phenyl)-ethyl)-piperazine (1.06g, 2.73 mmol), ammonium formate (861.0 mg, 13.66 mmol), 5% Pd/C (132.0mg), and ethanol (50 mL). Stir and heat the mixture at reflux. After 4hours 30 minutes, cool to ambient temperature and remove the catalyst byvacuum filtration through celite. Reduce the filtrate to residue andpurify it on silica gel using dichloromethane/2N ammonia in methanol(80:20) to give (443.8 mg, 78%) of the title compound as a white solid:mp 94-99° C.; mass spectrum (ion spray): m/z=209.3 (M+1); Analysis forC₁₂H₁₇FN₂: calcd: C, 69.20; H, 8.23; N, 13.45; found: C, 69.20; H, 8.26;N, 13.57.

Example 140 (S)-2-Phenethyl-piperazine

Combine (S)-1,4-dibenzyl-2-phenethyl-piperazine (5.15 g, 13.90 mmol),ammonium formate (4.38 g, 69.49 mmol), 5% Pd/C (672.5 mg), and ethanol(100 mL). Stir and heat the mixture at reflux. After 3 hours, cool toambient temperature and remove the catalyst by vacuum filtration throughcelite. Reduce the filtrate to residue and purify by silica gelchromatography using dichloromethane/7N ammonia in methanol (90:10) togive the title compound as a white solid: mp 116-119° C.; mass spectrum(ion spray): m/z=191.2 (M+1); Analysis for C₁₂H₁₈N₂: calcd: C, 75.74; H,9.53; N, 14.72; found: C, 75.90; H, 9.57; N, 14.59.

Example 141 (S)-1,4-Dibenyl-2-(2-(4-methoxy-phenyl)-ethyl)-piperazine

Combine (S)-1,4-dibenzyl-2-vinyl-piperazine (2.0 g, 6.84 mmol) and9-borabicyclo[3.3.1]nonane (82.1 mL, 41.04 mmol, 0.5 M in THF) and stirat ambient temperature. After 6 hours and 30 minutes, add1-iodo-4-methoxy-benzene (2.4 g, 10.26 mmol), triphenylphosphine (287.0mg, 1.09 mmol), tetrakis(triphenylphosphine) palladium(0)(158.0 mg, 0.14mmol), and 3N NaOH (5.6 mL) and stir at 60° C. After 22 hours, addethanolamine (10.0 ml) and dilute the mixture with water. Extract withethyl acetate and combine, wash (brine), dry (sodium sulfate), andreduce the extracts to residue. Purify the residue on silica gel usingethyl acetate/hexanes (5:95) to give a yellow oil. Dissolve the yellowoil in acetic acid/methanol (1:9) and apply to an SCX column. Wash thecolumn with methanol followed by 7N ammonia in methanol to give thetitle compound: mp 88-91° C.; mass spectrum (ion spray): m/z=401.4(M+1).

Example 142 (S)-1,4-Dibenzyl-2-(2-(3-methoxy-phenyl)-ethyl)-piperazine

Combine (S)-1,4-dibenzyl-2-vinyl-piperazine (2.0 g, 6.84 mmol) and9-borabicyclo[3.3.1]nonane (82.1 mL, 41.04 mmol, 0.5 M in THF) and stirat ambient temperature. After 6 hours and 30 minutes, add1-iodo-3-methoxy-benzene (2.4 g, 10.26 mmol), triphenylphosphine (287.0mg, 1.09 mmol), tetrakis(triphenylphosphine) palladium(0)(158.0 mg, 0.14mmol), and 3N NaOH (5.6 mL) and stir at 60° C. After 22 hours, addethanolamine (10.0 ml) and dilute the mixture with water. Extract withethyl acetate and combine, wash (brine), dry (sodium sulfate), andreduce the extracts to residue. Purify the residue on silica gel usingethyl acetate/hexanes (5:95) to give a yellow oil. Dissolve the yellowoil in acetic acid/methanol (1:9) and apply to an SCX column. Wash thecolumn with methanol followed by 7N ammonia in methanol to give thetitle compound: mp 73-75° C.; mass spectrum (ion spray): m/z=401.4(M+1).

Example 143 1,4-Dibenzyl-2-styryl-piperazine

Combine 1,4-dibenzyl-2-vinyl-piperazine (200.0 mg, 0.68 mmol), styrene(142.5 mg, 1.37 mmol), bis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride (168.8 mg, 0.21 mmol), and dichloromethane (8 mL) andstir at reflux. After 24 hours, the reaction mixture was filtered andreduced to residue. The title compound was observed by LC/MS: massspectrum (ion spray): m/z=369.1 (M+1); R_(f)=0.49 (hexanes/ethyl acetate(40:60)).

Example 144 1,4-Dibenzyl-2-styryl-piperazine

Combine tri-o-tolylphosphine (1.05 g, 3.46 mmol), palladium acetate (175mg, 0.78 mmol), triethylamine (3.26 mL, 23.4 mmol), iodobenzene (2.74mL, 24.5 mmol), 1,4-dibenzyl-2-vinyl-piperazine (3.26 g, 11.1 mmol) andacetonitrile (50 mL) in a sealable vessel and purge with nitrogen. Sealthe vessel and heat at 110° C. After 20 hours 45 minutes, cool toambient temperature and dilute with ethyl acetate. Filter and discardthe solids. Concentrate the filtrate and purify by silica gelchromatography using ethyl acetate-hexanes (0-100%) as the eluent togive the title compound: mass spectrum (ion spray): m/z=369 (M+1); ¹HNMR (DMSO-d₆): δ7.41 (d, 2H), 7.18-7.34 (m, 13 H), 6.64 (d, 1H), 6.27(dd, 1H), 3.94 (d, 1H), 3.46 (dd, 2H), 3.10 (d, 1H), 3.02 (dt, 1H),2.56-2.70 (m, 3H), 2.05-2.19 (m, 3H).

Example 145 1,4-Bis-(toluene-4-sulfonyl)-2-vinyl-piperazine

Combine tris(dibenzylideneacetone)dipalladium(0)-chloroform adduct (503mg, 0.49 mmol), racemic 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (606mg, 0.97 mmol) and tetrahydrofuran (100 mL) and stir at ambienttemperature. After 1 hour 30 minutes, add1,4-bis-(toluene-4-sulfonyl)-ethane (7.17 g, 19.5 mmol),cis-2-butene-1,4-diol diacetate (3.10 mL, 19.5 mmol) and tetrahydrofuran(100 mL) and heat at 40° C. After 18 hours, cool to ambient temperatureand concentrate under vacuum. Purify by silica gel chromatography usingethyl acetate-hexanes (20-60%) as the eluent. Recrystallize from ethylacetate-hexanes to give the title compound: mp 177-178° C.; massspectrum (ion spray): m/z=421 (M+1). Analysis calculated forC₂₀H₂₄N₂O₄S₂: C, 57.12; H, 5.75; N, 6.66. Found: C, 56.83; H, 5.26; N,6.62.

Example 146 2-Styryl-1,4-bis-(toluene-4-sulfonyl)-piperazine

Combine tri-o-tolylphosphine (72 mg, 0.24 mmol), palladium acetate (12mg, 0.05 mmol), triethylamine (0.22 mL, 1.6 mmol), iodobenzene (0.20 mL,1.83 mmol), 1,4-bis-(toluene-4-sulfonyl)-2-vinyl-piperazine (320 mg,0.76 mmol) and acetonitrile (8 mL) in a sealable vessel and purge withnitrogen. Seal the vessel and heat at 110° C. After 21 hours 45 minutes,cool to ambient temperature and dilute with ethyl acetate. Filter anddiscard the solids. Concentrate the filtrate and purify by silica gelchromatography using ethyl acetate-hexanes (0-30%) as the eluent to givea 8:1 ratio of the title compound to1,4-bis-(toluene-4-sulfonyl)-2-vinyl-piperazine: mass spectrum (ionspray): m/z=497(M+1); ¹H NMR(DMSO-d₆): δ7.59 (d, 2H), 7.53 (d, 2H), 7.42(d, 2H), 7.19-7.36 (m, 7 H), 6.48 (d, 1H), 6.08 (dd, 1H), 4.62 (m, 1H),3.70 (br d, 1H), 3.52 (m, 2H), 3.29 (dd, 1H), 2.41 (s, 3H), 2.29-2.32(m, 1H), 2.26 (s, 3H), 2.12 (dd, 1H).

Example 147 2-Phenethyl-piperazine

Combine 1,4-dibenzyl-2-styryl-piperazine (289 mg, 0.78 mmol), palladiumhydroxide (36 mg, 20 wt. % on carbon), and ethanol (100 mL) in ahydrogenation vessel. Shake and heat at 60° C. under a hydrogenatmosphere (60 psi). After 24 hours, cool to ambient temperature andfilter the palladium hydroxide. Concentrate the filtrate and purify bysilica gel chromatography using 2N ammonia in methanol-methylenechloride (20%) as the eluent to give the title compound: mass spectrum(ion spray): m/z=191(M+1); ¹H NMR (DMSO-d₆): δ7.11-7.31 (m, 5H),2.82-2.39 (m, 8H), 2.18 (dd, 1H), 1.48 (dd, 2H).

Example 148 (S)-1,4-Dibenzyl-2-(2-pyridin-3-yl-ethyl)-piperazine

Prepared by the method in Example 128, using 9-borabicyclo[3.3.1]nonane(68.4 mL, 34.2 mmol, 0.5 M in THF), (S)-1,4-dibenzyl-2-vinyl-piperazine(2.5 g, 8.55 mmol), triphenylphosphine (718 mg, 2.74 mmol),tetrakis(triphenylphosphine) palladium(0)(395 mg, 0.34 mmol),3-iodopyridine (2.63 g, 12.8 mmol) and 3M NaOH (7.0 mL, 21.0 mmol) togive title compound (1.28 g, 40%): mp 94-95.5° C.; mass spectrum (ionspray): m/z=372 (M+1). Analysis calculated for C₂₅H₂₉N₃: C, 80.82; H,7.87; N, 11.31. Found: C, 80.54; H, 7.76; N, 11.32.

Example 149 (S)-2-(2-Pyridin-3-yl-ethyl)-piperazine

Dissolve (S)-1,4-dibenzyl-2-(2-pyridin-3-yl-ethyl)-piperazine (1.6 g,4.31 mmol) in ethanol (30 mL). Add ammonium formate (1.63 g, 25.8 mmol)and palladium (240 mg, 5 wt. % on carbon) and heat to reflux. After 3hours 30 minutes, add additional ammonium formate (1.63 g, 25.8 mmol).After 3 hours, filter the palladium on carbon and concentrate thefiltrate. Slurry the residue in water and methylene chloride, basifywith 5N NaOH, and extract with methylene chloride andchloroform-isopropanol (3:1 mixture). Dry the extracts over sodiumsulfate, filter and concentrate the filtrate. Purify by silica gelchromatography using 7N ammonia in methanol-methylene chloride(2.5%-15%) as the eluent to give (261 mg, 32%) of the title compound: mp104-110° C.; mass spectrum (ion spray): m/z=192 (M+1). ¹H NMR (DMSO-d₆,D₂O): δ8.42 (d, 1H), 8.38 (dd, 1H), 7.63 (dt, 1H), 7.31 (dd, 1H),2.38-2.83 (m, 8H), 2.18 (dd, 1H), 1.50 (dd, 2H).

Example 150 Carbonic acid 4-methoxycarbonyloxy-but-2-enyl ester methylester

Combine methyl chloroformate (7.04 g, 80.0 mmol) in THF (70 mL) and adddropwise to a ice-water cold solution of 2-buten-1,4-diol (majority Zform) (19.7 g, 208 mmol) and pyridine (16.5 g, 208 mmol) in THF (150mL). Warm the mixture to room temperature and stir for 20 hours. Removethe pyridine salt by filtration and concentrate the filtrate to aresidue. Dissolve the residue with CH₂Cl₂ and wash sequentially with 1 NHCl and brine. Dry the organic layer over Na₂SO₄ and concentrate thesolvent in vacuo to give a residue. Purification by chromatography usinghexanes: EtOAc=12:1 as the eluents give the title compound: ¹H NMR(CDCl₃): δ5.82-5.79 (m, 2H), 4.75 (d, J=4.8 Hz, 4H),3.79 (s, 6H).

Example 151 1,2-Bis(p-tolysulfonolamino)ethane

Using ethylenediamine (72 g, 1.2 mol), p-toluenesulfonyl chloride (500g, 2.6 mol), sodium hydroxide (330 g, 8.25 mol), 6 N HCl (400 mL) andfollowing the procedure described in Caribb. J. Sci., 14, 77 (1974),gives the title compound as white solid.

Example 152 1,2-Bis(p-methoxybenzenesulfonylamino)ethane

Combine ethylenediamine (0.9 g, 15 mmol) in CH₂Cl₂ (50 mL) and mix withtriethylamine (3.03 g, 30 mmol). Cool the mixture on a ice-water bathand add dropwise 4-methoxybenzenesulfonyl chloride (6.2 g, 30 mmol) inCH₂Cl₂ (50 mL). Warm the reaction to room temperature and stirovernight. Wash the reaction with 1N HCl (100 mL), sat. NaHCO₃, brine,dry over Na₂SO₄, and concentrate the crude product in vacuo.Purification by flash chromatography (CH₂Cl₂/EtOAc=5:1) gives the titlecompound: Mass spectrum (electrospray): (m/z)=401.1 (M+1); ¹H NMR(CDCl₃): δ7.77-7.74 (m, 4H), 6.99-6.96 (m, 4H), 4.95 (br, 2H), 3.87 (s,6H), 3.06-3.04 (m, 4H).

Example 153 1,2-Bis(o-nitrobenzenesulfonylamino)ethane

By a method similar to Example 152, using ethylenediamine (0.9 g, 15mmol), triethylamine (3.03 g, 30 mmol), 2-nitrophenyl sulfonyl chloride6.63 g, 30 mmol) gives the title compound: Mass spectrum (electrospray):(m/z)=431.1 (M+1); ¹H NMR (DMSO-d₆): δ8.19 (br, 2H), 8.017.86 (m, 8H),3.00-2.99 (m, 4H).

Example 154 1.2-Bis(2,4,6-trimethylbenzenesulfonylamino)ethane

By a method similar to Example 152, using ethylenediamine (0.9 g, 15mmol), triethylamine (3.03 g, 30 mmol), 2-mesitylenesulfonyl chloride(6.56 g, 30 mmol) gives the title compound. Mass spectrum(electrospray): (m/z)=425.2 (M+1); ¹H NMR (DMSO-d₆): δ7.28 (br, 2H),7.01 (s, 4H), 2.69-2.68 (m, 4H), 2.47 (s, 12H), 2.28 (s, 6H).

Example 155 1,4-Bis(toluene-4-sulfonyl)-2-vinyl-piperazine

Combine tris(dibenzylideneacetone)dipalladium chloroform ((dba)₃Pd₂CHCl₃)(13 mg, “pd” 0.025 mmol) and racemic2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (BINAP, 15.6 mg, 0.025 mmol)in THF (2.5 mL) under N₂ and stir at room temperature. After 1 hour, add1,2-bis(p-toylsulfonylamine) ethane (184 mg, 0.5mmol),(Z)-1,4-bis(methoxycarbonyloxy)but-2-ene (102 mg, 0.5 mmol), andTHF (2.5 mL) and heat to 40° C. After 24 hours, cool to room temperatureand concentrate the reaction under reduced pressure to give a brownsolid. Wash the solid with ether (3×5 mL), dissolve in CH₂Cl₂, passthrough a plug of silica gel to remove insoluble material andconcentrate the filtrate. Purification by Chiral HPLC: ChiralpakAD(0.46×25 cm), IPA:Heptane 40:60, 1 mL/min, Retention Time: 14.53,18.01 min or by flash chromatography on silica gel, gradient: CH₂Cl₂ to2.5% EtOAc in CH₂Cl₂ to give the title compound: ¹H NMR (CDCl₃):δ7.60-7.56 (m, 4H), 7.35-7.32 (m, 2H), 7.26-7.23 (m, 2H), 5.7 (ddd, 1H,J=6.4 Hz, J=10.1 Hz, J=17.2 Hz), 5.30-5.17 (m, 2H), 4.45 (br, 1H),3.66-3.55 (m, 3H), 3.23 (dt, 1H, J=3.1 Hz, J=11.9 Hz), 2.57 (dd, 1H,J=3.1 Hz, J=11.5 Hz), 2.47-2.43, (m, 1H), 2.47 (s, 3H), 2.40 (s, 3H).

By a method similar to Example 155, the following examples wereprepared:

No.: X Data 156 4-OCH₃ Mass spectrum(electrospray): (m/z)=453.2(M+1); ¹HNMR: δ7.65-7.60(m, 4H), 7.00-6.89(m, 4H), 5.75(ddd, 1H, J=6.3Hz,J=10.5Hz, J=17.4Hz), 5.30- 5.19(m, 2H), 4.44(br, 1H), 3.89(s, 3H),3.85(s, 3H), 3.63-3.53(m, 3H), 3.23(dt, 1H, J=3.0Hz, J=12.0Hz), 2.56(dd,1H), J=3.7Hz, J=11.5Hz), 2.40(dt, 1H, J=3.1Hz, J=11.3Hz). Chiral HPLC:Chiralpak AD (0.46 × 25 cm), IPA:Heptane = 40:60, 1 mL/min, RetentionTime: 21.00, 25.9 min. 157 2,4,6-tri- Mass spectrum(electrospray):(m/z)=477.3(M+1); methyl ¹H NMR (CDCl₃): δ6.95(s, 4H), 5.83-5.72(m, 1H),5.16-5.00(m, 2H), 4.40(br, 1H), 3.47-3.28(m, 4H), 3.14(dd, 1H, J=3.5Hz,J=11.9Hz), 2.83(dt, 1H, J=3.8Hz, J=11.1Hz), 2.59(s, 12H), 2.30(s, 6H).Chiral HPLC: Chiralpak AD(0.46 × 25 cm), IPA:Heptane = 20:80, 1 mL/min,Retention Time: 8.43, 9.05 min. 158 2-NO₂ Mass spectrum(electrospray):(m/z)=483.1(M+1; ¹H NMR (CDCl₃): δ8.07-8.04(m, 1H), 7.94- 7.91(m, 1H),7.74-7.60(m, 6H), 5.83(m, 1H), 5.32-5.22(m, 2H), 4.63(br, 1H),3.95-3.71(m, 3H), 3.49(dt, 1H, J=3.2Hz, J=11.9Hz), 3.15(dt, 1H, J=3.7Hz,J=12.7Hz), 2.86(dt, 1H, J=3.4Hz, J=12.2Hz). Chiral HPLC: ChiralpakAD(0.46 × 25 cm), 100% EtOH, 1 mL/min, Retention Time: 8.92, 10.67 min.

By a method similar to Example 155, the following asymmetric productswere obtained using (dba)₃Pd₂CHCl₃,(26 mg, “Pd“:0.05 mmol), (R)-BINAP(31.2 mg, 0.05 mmol), 1,2-bis(p-toylsulfonylamini)ethane(368 mg, 1.0mmol) and (Z)-1,4-bis(methoxycarbonyloxy)but-2-ene (204 mg, 1.0 mmol).

No.: X Yield % ee % 159 p-Me 84 74.9(S) 160 p-OMe 85 73.9 1612,4,6-TriMe 70 77.0 162 2-NO₂ 39 65.3

Example 163 2-Phenethyl-1,4-bis-(toluene-4-sulfonyl)-piperazine

Add 9-BBN (0.5 M THF solution, 13.7 mL, 6.85 mmol) to a 100 mL schlenkflask containing (S)-1,4-bis(toluene-4-sulfonyl)-2-vinyl-piperazine(0.96g, 2.3 mmol) in THF (5 mL), at room temperature under nitrogen and stir.After 18 hours, treat the reaction with tetrakis(triphenylphosphine)palladium (53 mg, 0.046 mmol), triphenyl phosphine (94.6 mg, 0.36 mmol),iodiobenzene (0.703 g, 3.4 mmol) and 3N NaOH (2.8 mL, 8.4 mmol) and heatto reflux. After 24 hours, cool the reaction to room temperature, removein vacuo the THF solvent, dilute the residue with CH₂Cl₂, wash with 1NHCl, brine, and dry over Na₂SO₄. Purification by flash chromatographytwice (Gradient: Hexanes/CH₂Cl₂=50/50, toHexanes/CH₂Cl₂/EtOAc=40/40/10), and recrystallization in MeOH gives 860mg (75%) of the title compound: mass spectrum (electrospray):(m/z)=499.2 (M+1); ¹H NMR (CDCl₃): δ7.58-7.54 (m, 4H), 7.33-7.20 (m,7H), 7.19-7.07 (m, 2H), 3.99 (m, 1H), 3.81-3.78 (m, 1H), 3.64-3.60 (m,2H), 3.22 (dt, 1H, J=3.2 Hz, J=12.4 Hz), 2.57-2.41 (m, 2H), 2.41 (s,3H), 2.33 (s, 3H), 2.33-2.20 (m, 2H), 2.03-1.98 (m, 1H), 1.75-1.63 (m,1H).

Example 164 2-Phenethyl-piperazine

Add 2-phenethyl-1,4-bis-(toluene-4-sulfonyl)-piperazine (100 mg, 0.2mmol) in THF (2 mL) to a cooled (−78° C.) suspension of metallic Na(36.8 mg, 1.6 mmol) and naphthalene (230.4 mg, 1.8 mmol) in freshdistilled THF(4 mL) was under nitrogen and stir at −78° C. After 1 hour,TLC indicated the reaction is complete. Hydrolyze the reaction withbrine (10 mL) and extract with CH₂Cl₂ (3×10 mL). Combine the organiclayers and dry over Na₂SO₄ and evaporate. Pass the resulting residuethrough a SCX column to obtain the title compound as a solid: massspectrum (electrospray): (m/z)=191.2 (M+1); ¹H NMR (CDCl₃): δ7.30-7.25(m, 2H), 7.20-7.15 (m, 3H), 3.00-2.61 (m, 8H), 2.40 (t, 1H, J=11.7 Hz),1.70 (br, 2H), 1.67-1.60 (m, 2H).

Example 171 (S)-1,4-Dibenzyl-2-phenethyl-piperazine

Combine (S)-1,4-dibenzyl-2-vinyl-piperazine (4.9 g, 16.63 mmol) and9-borabicyclo[3.3.1]nonane (199.6 ml, 99.78 mmol, 0.5 M in THF) and stirat ambient temperature. After 24 hours, add iodo-benzene (5.1 g, 24.95mmol), triphenylphosphine (697.9 mg, 2.66 mmol),tetrakis(triphenylphosphine) palladium(0)(384.3 mg, 0.33 mmol), and 3NNaOH (13.7 mL) and stir at 60° C. After 22 hours, dilute the mixturewith ethyl acetate and wash it with 1N sulfuric acid. Adjust the pH to14, extract with ethyl acetate, and combine, wash (brine), dry (sodiumsulfate), and reduce the extracts to residue. Purify the residue onsilica gel using a ethyl acetate/hexanes gradient (5:95 to 10:90) togive (5.15 g, 84%) of the title compound as a white solid: mp 86-90° C.;mass spectrum (ion spray): m/z=371.3 (M+1).

Example 172 (S)-1,4-Dibenzyl-2-(2-(2-methoxy-pheny)-ethyl)-piperazine

Combine (S)-1,4-dibenzyl-2-vinyl-piperazine (2.5 g, 8.55 mmol) and9-borabicyclo[3.3.1]nonane (68.4 mL, 34.20 mmol, 0.5 M in THF) and stirat ambient temperature. After 24 hours, add 1-iodo-2-methoxy-benzene(3.0 g, 12.82 mmol), triphenylphosphine (358.8 mg, 1.37 mmol),tetrakis(triphenylphosphine) palladium(0) (197.5 mg, 0.17 nmol), and 3NNaOH (7.0 mL) and stir at 60° C. After 22 hours, remove the THF undervacuum, stir the residue in 2N NaOH, and extract with diethyl ether.Wash the organic with 1N H₂SO₄ then adjust the aqueous to pH 14. Extractthe aqueous with diethyl ether and combine, wash (brine), dry (sodiumsulfate), and reduce the extracts to residue. Purify the residue onsilica gel using ethyl acetate/hexanes (5:95) to give (2.21 g, 65%) ofthe title compound: mp 58-61 C°; mass spectrum (ion spray): m/z=401.3(M+1); Analysis for C₂₇H₃₂N₂O: calcd: C, 80.96; H, 8.05; N, 6.99; found:C, 81.08; H, 7.99; N, 7.10.

Example 173 (S)-2-(2-(4-Methoxy-phenyl)-ethyl)-piperazine

Combine (s)-1,4-dibenzyl-2-(2-(4-methoxy-phenyl)-ethyl)-piperazine (1.34g, 3.33 mmol), ammonium formate (1.05 g, 16.67 mmol), 5% Pd/C (161.2mg), and ethanol (100 mL). Stir and heat the mixture at reflux. After 3hours, cool to ambient temperature and remove the catalyst by vacuumfiltration through celite. Reduce the filtrate to residue and purify iton silica gel using dichloromethane/2N ammonia in methanol (80:20) togive (689.3 mg, 94%) of the title compound as a white solid: mp 125-130°C.; mass spectrum (ion spray): m/z=221.1 (M+1); Analysis for C₁₃H₂₀N₂O:calcd: C, 70.87; H, 9.15; N, 12.72; found: C, 70.58; H, 9.05; N, 12.61.

Example 174 (S)-2-(2-(3-Methoxy-phenyl)-ethyl)-piperazine

Combine (S)-1,4-dibenzyl-2-(2-(3-methoxy-phenyl)-ethyl)-piperazine (2.15g, 5.37 mmol), ammonium formate (1.69 g, 26.84 mmol), 5% Pd/C (259.7mg), and ethanol (100 mL). Stir and heat the mixture at reflux. After 3hours, cool to ambient temperature and remove the catalyst by vacuumfiltration through celite. Reduce the filtrate to residue and purify iton silica gel using dichloromethane/7N ammonia in methanol (90:10) togive (1.11 g, 94%) of the title compound as a white solid: mp 53-57° C.;mass spectrum (ion spray): m/z=221.1 (M+1); Analysis for C₁₃H₂₀N₂O:calcd: C, 70.87; H, 9.15; N, 12.72; found: C, 70.52; H, 9.06; N, 12.74.

Example 175 (S)-2-(2-(2-methoxy-phenyl)-ethyl)-piperazine

Combine (S)-1,4-dibenzyl-2-(2-(2-methoxy-phenyl)-ethyl)-piperazine (2.10g, 5.24 mmol), ammonium formate (1.65 g, 26.19 mmol), 5% Pd/C (253.6mg), and ethanol (100 mL). Stir and heat the mixture at reflux. After 3hours, cool to ambient temperature and remove the catalyst by vacuumfiltration through celite. Reduce the filtrate to residue and purify iton silica gel using dichloromethane/2N ammonia in methanol (80:20) togive (1.00 g, 87%) of the title compound: mass spectrum (ion spray):m/z=221.1 (M+1).

Example 17610-((S)-3-(2-(4-Fluorolphenyl)-ethyl)-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulenedihydrochloride

Combine 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylaminehydrochloride (492.9 mg, 1.85 mmol),(s)-2-(2-(4-fluoro-phenyl)-ethyl)-piperazine (772.6 mg, 3.71 mmol),N,N-diisopropylethylamine (239.7 mg, 1.85 mmol), DMSO (0.82 ml), andtoluene (3.3 mL). Stir and heat the mixture at 105° C. After 48 hours,cool the mixture to ambient temperature and then dilute it with ethylacetate and water. Remove the organic layer and wash it with 1N NaOH andbrine. Dry (sodium sulfate) and concentrate the organic layer toresidue. Purify the residue on silica gel using dichloromethane/methanol(95:5) to give (376.0 mg, 48%) of a brown foam. Prepare thedihydrochloride salt in ethyl acetate: mp 236° C., dec; mass spectrum(ion spray): m/z=421.2 (M+1).

Example 17710-((S)-3-(2-(3-Fluoro-phenyl)-ethyl)-piperazin-1-yl))-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulenedihydrochloride

Combine 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylaminehydrochloride (696.7 mg, 2.62 mmol),(S)-2-(2-(3-fluoro-phenyl)-ethyl)-piperazine (1.09 g, 5.24 mmol),N,N-diisopropylethylamine (338.8 mg, 2.62 mmol), DMSO (1.2 ml), andtoluene (4.6 mL). Stir and heat the mixture at 105° C. After 48 hours,cool the mixture to ambient temperature and then dilute it with ethylacetate and water. Remove the organic layer and wash it with 1N NaOH andbrine. Dry (sodium sulfate) and concentrate the organic layer toresidue. Purify the residue on silica gel using dichloromethane/methanol(95:5) to give (526.8 mg, 48%) of a dark brown oil. Prepare thedihydrochloride salt in ethyl acetate: mp 211° C., dec; mass spectrum(ion spray): m/z=421.2 (M+1).

Example 17810-((S)-3-(2-(2-Fluoro-phenyl)-ethyl)-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulenedihydrochloride

Combine 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylaminehydrochloride (645.8 mg, 2.43 mmol),(S)-2-(2-(2-fluoro-phenyl)-ethyl)-piperazine (1.01 g, 4.86 mmol),N,N-diisopropylethylamine (314.1 mg, 2.43 mmol), DMSO (1.1 ml), andtoluene (4.3 mL). Stir and heat the mixture at 105° C. After 48 hours,cool the mixture to ambient temperature and then dilute it with ethylacetate and water. Remove the organic layer and wash it with 1N NaOH andbrine. Dry (sodium sulfate) and concentrate the organic layer toresidue. Purify the residue on silica gel using dichloromethane/methanol(95:5) to give (481.7 mg, 47%) of a brown foam. Prepare thedihydrochloride salt in ethyl acetate: mp 209°, dec; mass spectrum (ionspray): m/z=421.2 (M+1).

Example 17910-((S)-3-(2-(4-methoxy-phenyl)-ethyl)-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulenedihydrochloride

Combine 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylaminehydrochloride (620.0 mg, 2.33 mmol),(S)-2-(2-(4-methoxy-phenyl)-ethyl)-piperazine (1.03 g, 4.67 mmol),N,N-diisopropylethylamine (301.5 mg, 2.33 mmol), DMSO (1.0 mL), andtoluene (4.0 mL). Stir and heat the mixture at 105° C. After 48 hours,cool the mixture to ambient temperature and then dilute it with ethylacetate and water. Remove the organic layer and wash it with 1N NaOH andbrine. Dry (sodium sulfate) and concentrate the organic layer toresidue. Purify the residue on silica gel using dichloromethane/methanol(95:5) to give (703.8 mg, 70%) of a brown oil. Prepare thedihydrochloride salt in ethyl acetate: mp 213° C., dec; mass spectrum(ion spray): m/z=433.1 (M+1).

Example 18010-((S)-3-(2-(3-Methoxy-phenyl)-ethyl)-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulenedihydrochloride

Combine 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylaminehydrochloride (301.6 mg, 1.13 mmol),(S)-2-(2-(3-methoxy-phenyl)-ethyl)-piperazine (500.0 mg, 2.27 mmol),N,N-diisopropylethylamine (146.7 mg, 1.13 mmol), DMSO (0.5 mL), andtoluene (2.0 mL). Stir and heat the mixture at 105° C. After 64 hours,cool the mixture to ambient temperature and then dilute it with aceticacid/methanol (1:9) and apply it to an SCX column. Wash the column withmethanol to remove impurities. Treat the column with 7N ammonia inmethanol to elude the product. Evaporate the solvent to residue. Purifythe residue on silica gel using dichloromethane/methanol (95:5) to give(279.0 mg, 57%) of a brown foam. Prepare the dihydrochloride salt inethyl acetate: mp 201° C., dec; mass spectrum (ion spray): m/z=433.3(M+1).

Example 18110-((S)-3-(2-(2-Methoxy-phenyl)-ethyl)-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaz-benzo[f]azulenedihydrochloride

Combine 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylaminehydrochloride (1.17 g, 4.42 mmol),(s)-2-(2-(2-methoxy-phenyl)-ethyl)-piperazine (973.5 mg, 4.42 mmol),N,N-diisopropylethylamine (571.1 mg, 4.42 mmol), DMSO (2.0 mL), andtoluene (8.0 mL). Stir and heat the mixture at 105° C. After 48 hours,cool the mixture to ambient temperature and then dilute it with ethylacetate and water. Remove the organic layer and wash it with 1N NaOH andbrine. Dry (sodium sulfate) and concentrate the organic layer toresidue. Purify the residue on silica gel using dichloromethane/methanol(95:5) to give (473.9 mg, 25%) of a brown foam. Prepare thedihydrochloride salt in ethyl acetate: mp 202° C., dec; mass spectrum(ion spray): m/z=433.1 (M+1).

Example 18210-((S)-3-(2-(4-Fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulenedihydrochloride

Combine10-((S)-3-(2-(4-fluoro-phenyl)-ethyl)-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene(259.0 mg, 0.62 mmol), formaldehyde (55.0 μL, 0.68 mmol, 37% in water),and 1,2-dichloroethane (20.0 mL). Stir the mixture at ambienttemperature for 5 minutes and then add sodium triacetoxyborohydride(195.8 mg, 0.92 mmol). After stirring for 30 minutes at ambienttemperature, quench the reaction with saturated sodium bicarbonate.Remove the organic portion, extract the aqueous with dichloromethane andcombine, wash (brine), dry (sodium sulfate), and reduce the extracts toresidue. Purify the residue on silica gel using dichloromethane/methanol(95:5) to give (236.7 mg, 89%) of a brown foam. Prepare thedihydrochloride salt in ethyl acetate: mp 253° C., dec; mass spectrum(ion spray): m/z=435.1 (M+1).

Example 18310-((S)-3-(2-(3-Fluoro-phenyl)-ethyl)-4-methyl-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulenedihydrochloride

Combine10-((S)-3-(2-(3-fluoro-phenyl)-ethyl)-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene(265.6 mg, 0.63 mmol), formaldehyde (56.4 μL, 0.69 mmol, 37% in water),and 1,2-dichloroethane (20.0 mL). Stir the mixture at ambienttemperature for 5 minutes and then add sodium triacetoxyborohydride(200.7 mg, 0.95 mmol). After stirring for 30 minutes at ambienttemperature, quench the reaction with saturated sodium bicarbonate.Remove the organic portion, extract the aqueous with dichloromethane andcombine, wash (brine), dry (sodium sulfate), and reduce the extracts toresidue. Purify the residue on silica gel using dichloromethane/methanol(95:5) to give (215.4 mg, 79%) of a brown oil. Prepare thedihydrochloride salt in ethyl acetate: mp 225° C., dec; mass spectrum(ion spray): m/z=435.1 (M+1).

Example 18410-((S)-3-(2-(2-Fluoro-phenyl)-ethyl)-4-methyl-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulenedihydrochloride

Combine10-((S)-3-(2-(2-fluoro-phenyl)-ethyl)-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene(240.0 mg, 0.57 mmol), formaldehyde (50.9 μL, 0.63 mmol, 37% in water),and 1,2-dichloroethane (20.0 mL). Stir the mixture at ambienttemperature for 5 minutes and then add sodium triacetoxyborohydride(181.4 mg, 0.86 mmol). After stirring for 30 minutes at ambienttemperature, quench the reaction with saturated sodium bicarbonate.Remove the organic portion, extract the aqueous with dichloromethane andcombine, wash (brine), dry (sodium sulfate), and reduce the extracts toresidue. Purify the residue on silica gel using dichloromethane/methanol(95:5) to give (247.9 mg, 100%) of a brown oil. Prepare thedihydrochioride salt in ethyl acetate: mp 203° C., dec; mass spectrum(ion spray): m/z=435.3 (M+1).

Example 18510-((S)-3-(2-(4-Methoxy-phenyl)-ethyl)-4-methyl-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulenedihydrochloride

Combine10-((S)-3-(2-(4-methoxy-phenyl)-ethyl)-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene(159.2 mg, 0.37 mmol), formaldehyde (32.9 μL, 0.41 mmol, 37% in water),and 1,2-dichloroethane (20.0 mL). Stir the mixture at ambienttemperature for 5 minutes and then add sodium triacetoxyborohydride(117.0 mg, 0.55 mmol). After stirring for 30 minutes at ambienttemperature, quench the reaction with saturated sodium bicarbonate.Remove the organic portion, extract the aqueous with dichloromethane andcombine, wash (brine), dry (sodium sulfate), and reduce the extracts toresidue. Purify the residue on silica gel using dichloromethane/methanol(95:5) to give (158.4 mg, 96%) of a brown foam. Prepare thedihydrochloride salt in ethyl acetate: mp 239° C., dec; mass spectrum(ion spray): m/z=447.2 (M+1).

Example 18610-((S)-3-(2-(3-Methoxy-phenyl)-ethyl)-4-methyl-piperazin-1-yl)-2-methyl-4H-3-thia-4.9-diaza-benzo[f]azulenedihydrochloride

Combine10-((S)-3-(2-(3-methoxy-phenyl)-ethyl)-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene(279.0 mg, 0.65 mmol), formaldehyde (57.6 μL, 0.71 mmol, 37% in water),and 1,2-dichloroethane (20.0 mL). Stir the mixture at ambienttemperature for 5 minutes and then add sodium triacetoxyborohydride(205.0 mg, 0.97 mmol). After stirring for 30 minutes at ambienttemperature, quench the reaction with saturated sodium bicarbonate.Remove the organic portion, extract the aqueous with dichloromethane andcombine, wash (brine), dry (sodium sulfate), and reduce the extracts toresidue. Purify the residue on silica gel using dichloromethane/methanol(95:5) to give (278.7 mg, 97%) of a brown oil. Prepare thedihydrochloride salt in ethyl acetate:mp 200° C., dec; mass spectrum(ion spray): m/z=447.1 (M+1).

Example 18710-((S)-3-(2-(2-Methoxy-phenyl)-ethyl)-4-methyl-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulenedihydrochloride

Combine10-((S)-3-(2-(2-methoxy-phenyl)-ethyl)-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene(209.2 mg, 0.48 mmol), formaldehyde (43.2 μL, 0.53 mmol, 37% in water),and 1,2-dichloroethane (20.0 mL). Stir the mixture at ambienttemperature for 5 minutes and then add sodium triacetoxyborohydride(153.7 mg, 0.73 mmol). After stirring for 30 minutes at ambienttemperature, quench the reaction with saturated sodium bicarbonate.Remove the organic portion, extract the aqueous with dichloromethane andcombine, wash (brine), dry (sodium sulfate), and reduce the extracts toresidue. Purify the residue on silica gel using dichloromethane/methanol(95:5) to give (191.6 mg, 89%) of a brown foam. Prepare thedihydrochloride salt in ethyl acetate: mp 213° C., dec; mass spectrum(ion spray): m/z=447.2 (M+1).

Example 1882-Methyl-10-(4-methyl-(S)-3-(2-pydridin-4-yl-ethyl)-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulenetrihydrochloride hydrate

Combine2-methyl-10-((S)-3-(2-pyridin-4-yl-ethyl)-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene(380 mg, 0.94 mmol) and formaldehyde (82 μL, 1.04 mmol, 37% in water),and methylene chloride (10 mL). Stir 5 minutes at ambient temperature.Add sodium triacetoxyborohydride (300 mg, 1.41 mmol) and stir 30 minutesat ambient temperature. Dilute with saturated sodium bicarbonatesolution and extract with methylene chloride. Dry the extracts withsodium sulfate, filter and concentrate the filtrate. Purify by silicagel chromatography using 2N ammonia in methanol-methylene chloride(1%-3%) as the eluent to give 345 mg of a brown foam. Purify again bysilica gel chromatography using 2N ammonia in methanol-methylenechloride (0%-6.5%) as the eluent to give the free base. Crystallize asthe trihydrochloride salt from ethyl acetate and ethanol to give thetitle compound (244 mg, 62%): mp 214-217° C. dec.; mass spectrum (ionspray): m/z=418 (M+1), 416 (M−1). Analysis calculated forC₂₄H₂₇N₅S.3HCl·0.9H₂O: C, 53.07; H, 5.90; N, 12.89. Found: C, 53.31; H,5.54; N, 12.75.

Example 189 2-Methyl-10-((S)-3-(2-pyridin-3-yl-ethyl)-piperazin-1-yl-4H-3-thia-4,9-diaza-benzo[f]azulene trihydrochloride dihydrate

Combine (S)-2-(2-pyridin-3-yl-ethyl)-piperazine (2.0 g, 10.5 mmol),2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine (2.4 g, 10.5mmol), acetic acid (0.1 mL), toluene (21 mL), and DMSO (5 mL). Heat at110° C. Purge periodically with nitrogen and replace condensor after 4hours. After 41 hours 30 minutes, cool to ambient temperature and dilutewith ethyl acetate and water. Extract with ethyl acetate. Wash theextracts with water and brine, dry over sodium sulfate, filter andconcentrate the filtrate. Purify by silica gel chromatography using 2Nammonia in methanol-methylene chloride (0%-5%) as the eluent to give thefree base. Purify 600 mg by radial silica gel chromatography using a 2mm plate and 2N ammonia in methanol-methylene chloride (1%-4%) as theeluent to give the free base. Crystallize as the trihydrochloride saltfrom ethyl acetate and ethanol to give the title compound: mp 226-229°C. dec.; mass spectrum (ion spray): m/z=404 (M+1), 402 (M−1). Analysiscalculated for C₂₃H₂₅N₅S.3HCl.2H₂O: C, 50.32; H, 5.88; N, 12.76. Found:C, 50.32; H, 5.97; N, 12.71.

Example 1902-Methyl-10-(4-methyl-(S)-3-(2-pyridin-3-yl-ethyl)-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine2-methyl-10-((S)-3-(2-pyridin-3-yl-ethyl)-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene(728 mg, 1.80 mmol) and formaldehyde (158 μL, 1.98 mmol, 37% in water),and methylene chloride (30 mL). Stir 10 minutes at ambient temperature.Add sodium triacetoxyborohydride (573 mg, 2.70 mmol) and stir 1 hour atambient temperature. Dilute with saturated sodium bicarbonate solutionand extract with methylene chloride. Dry the extracts with sodiumsulfate, filter and concentrate the filtrate. Purify by silica gelchromatography using 2N ammonia in methanol-methylene chloride (0%-4%)as the eluent to give the title compound (595 mg, 79%): Mass spectrum(ion spray): m/z=418 (M+1), 416 (M−1). Analysis calculated forC₂₄H₂₇N₅S: C, 69.03; H, 6.52; N, 16.77. Found: C, 68.92; H, 6.60; N,16.65.

Example 1912-Methyl-10-(4-methyl-(S)-3-(2-pyridin-2-yl-ethyl)-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulenetrihydrochloride

Combine2-methyl-10-((S)-3-(2-pyridin-2-yl-ethyl)-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene(200 mg, 0.50 mmol) and formaldehyde (43 μL, 0.54 mmol, 37% in water),and methylene chloride (5 mL). Stir 10 minutes at ambient temperature.Add sodium triacetoxyborohydride (158 mg, 0.74 mmol) and stir 1 hour atambient temperature. Dilute with saturated sodium bicarbonate solutionand extract with methylene chloride. Dry the extracts with sodiumsulfate, filter and concentrate the filtrate. Purify by silica gelchromatography using 2N ammonia in methanol-methylene chloride (0%-4%)as the eluent to give the free base. Crystallize as the trihydrochloridesalt from ethyl acetate and ethanol to give the title compound (161 mg,78%): Mass spectrum (ion spray): m/z=418 (M+1), 416 (M−1). Analysiscalculated for C₂₄H₂₇N₅S.3HCl: C, 54.70; H, 5.74; N, 13.29. Found: C,54.88; H, 6.02; N, 12.96.

Example 192 (S)-1,4-Dibenzyl-2-(4-phenyl-but-3-enyl)-piperazine

Combine 9-borabicyclo[3.3.1]nonane (81.6 mL, 40.3 mmol, 0.5 M in THF)and (S)-1,4-dibenzyl-2-vinyl-piperazine (2.0 g, 6.8 mmol)and stir atambient temperature. After 16 hours, take half volume of it, addtriphenylphosphine (143 mg, 0.55 mmol),tetrakis(triphenylphosphine)palladium(0) (78.5 mg, 0.068 mmol), andbeta-bromostyrene (0.93 g, 5.08 mmol). Add 3N NaOH (2.8 mL, 8.8 mmol)slowly, gas evolution will occur. Heat to reflux. After 24 hours, coolto ambient temperature. Remove the solvent under reduced pressure,dilute with diethyl ether, wash with 1N HCl, 1N NaOH, H₂O and brine, drythe organic layer over Na₂SO₄, filter and concentrate under reducedpressure. Purification by flash chromatography on silica gel using 2Nammonia in methanol-methylene chloride (0.5%-3%) as the eluent, collectcompound and pass through 10 g SCX column, using MeOH, 0.2 N NH₃ in MeOHas eluent to give the title compound (750 mg, 56%): mass spectrum(electrospray): m/z=397.3 (M+1); ¹H NMR (300 MHz, CDCl₃): δ7.35-7.16 (m,15H), 6.36-6.12 (m, 2H), 4.01 (d, 1H, J=13.2), 3.56-3.43 (m, 2H), 3.25(d, 1 H, J=13.4 Hz), 2.75-2.68 (m, 2H), 2.56-2.48 (m, 2H), 2.29-2.13 (m,5H), 1.82-1.76 (m, 2H).

Example 193 (S)-2-(4-Phenyl-butyl)-piperazine

Combine (S)-1,4-dibenzyl-2-(4-phenyl-but-3-enyl)-piperazine (2.12 g, 5.3mmol), 10% Pd/C (300 mg, 0.027 mmol) and ammonia formate (1.67 g, 26.5inmol) in EtOH (50 mL), heat to reflux for 3 hours 30 minutes, and coolto room temperature. Remove the catalyst via filtration, and concentratethe filtrate to a residue. Purification by flash chromatography onsilica gel using 2N NH₃ in MeOH and dichloromethane (5%-15%) to give thetitle compound (780 mg, yield 67%): mass spectrum (Electrospray):m/z=219.2 (M+1); ¹H NMR (CDCl₃): δ7.30-7.15 (m, 5H), 2.96-2.55 (m, 8H),2.37-2.30 (m, 1H), 1.64-1.60 (m, 2H), 1.39-1.29 (m, 4H).

Example 194(S)-2-Methyl-10-(3-(4-phenyl-butyl-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene,dihydrochloric acid

Combine (S)-2-(4-phenyl-butyl)-piperazine (820 mg, 3.76 mmol),2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine (861 mg, 3.76mmol), 1-methyl-2-pyrrolidinone (7 mL), and heat at 220° C. After 4hours, cool to ambient temperature, pass through SCX column (10 G), andcollect the fraction of 0.2 NH₃ in methanol. Purification by silica gelchromatography of the crude product using 2N ammonia inmethanol-dichloromethane (2%-4%) as the eluent to give 310 mg brown foamof the free base: mass spectrum (Electronspray): m/z=431.3 (M+1); ¹H NMR(300 MHz, CDCl₃): δ7.30-7.15 (m, 5 H), 7.04-6.84 (m, 3H), 6.60 (dd, 1H,J=1.3, J=7.7 Hz), 6.28 (d, 1H, J=1.2 Hz), 4.95 (s, 1H), 4.06-3.96 (m,2H), 3.05-2.89 (m, 2H), 2.77-2.74 (m, 1H), 2.65-2.49 (m, 3H), 2.30 (d,3H, J=1.1 Hz), 1.64 (m, 2H), 1.45-1.37 (m, 4H). Pass this productthrough a SCX column (5 g), eluent with 0.6 M CH₃COCl/EtOH, concentrateto give yellow foam, treat with 15 mL of CH₃CN/H₂O=50/50, and lyophilizeovernight to give yellow gold solid of title compound: mass spectrum(Electrospray): m/z=431.1 (M+1-2HCl, 429.1 (M−1-2HCl); Analysiscalculated for C₂₆H₃₀N₄S.2HCl.1.6 H₂O: C, 58.66; H, 6.66; N, 10.52.Found: C, 58.34; H, 6.47; N, 10.16.

Example 195(S)-2-Methyl-10-(3-(4-phenyl-butyl)-4-methyl-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene,dihydrochloric acid

Combine(s)-2-methyl-10-3-(4-phenyl-butyl)-piperazin-1-yl]-4H-3-thia-4,9-diaza-benzo[f]azulene(230 mg, 0.53 mmol), formaldehyde (37% aq, 47 mg, 0.58 mmol) and sodiumtriacetoxyborohydride (168.5 mg, 0.795 mmol) in 1,2-dichloroethane (15mL) and stir at room temperature. After 2 hours, quench the reaction byadding sat. NaHCO₃, extract the aqueous solution with CH₂Cl₂ (3×10 mL),wash the organic solvent with brine and dry over Na₂SO₄. Concentrate thesolvent in vaccuo to give a residue and purify by silica gelchromatography using 2N ammonia in methanol-dichloromethane (2%-4%) asthe eluent to give (170 mg, 72%) light brown foam of the free base: massspectrum (Electrospray): m/z=445.2 (M+1); ¹H NMR (400 MHz, CDCl₃):δ7.29-7.15 (m, 5 H), 7.03-6.85 (m, 3 H), 6.60 (dd, 1H, J=1.5, J=7.8 Hz),6.28 (d, 1H, J=1.0 Hz), 4.95 (s, 1H), 3.98-3.85 (m, 2H), 3.15-3.08 (m,1H), 2.86-2.75 (m, 3H), 2.64-2.59 (m, 2H), 2.36-28 (m, 8H), 2.10-2.04(m, 1H), 1.66-1.35 (m, 4H). Treat the free base with acetyl chloride(2.2 eq) in ethanol for 1hour 30 minutes at room temperature, remove thesolvent, dissolve in solvent (15 mL) CH₃CN/H₂O=50/50, lyophilizeovernight to give yellow solid of title compound: mass spectrum(Electrospray): m/z=445.2 (M+1-2HCl), 443.2 (M−1-2HCl). Analysiscalculated for C₂₇H₃₂N₄S.2HCl.0.6 H₂O: C, 61.38; H, 6.71; N, 10.60.Found: C, 61.38; H, 6.44; N, 10.54.

Example 196 (S)-4-Benzyl-2-(2-hydroxy-ethyl)-piperazine-1-carboxylicacid tert-butyl ester

Dissolve commercial N-tBoc-L-aspartic acid beta-methyl ester (40 g, 0.16moles) in dichloromethane (800 mL); cool to 0° C. and addN-benzylglycine methyl ester (28 g, 0.15 moles) as a solution in 100 mLof dichloromethane, followed sequentially by N,N-diisopropylethylamine(28 mL, 0.16 moles), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (EDAC, 31 g, 0.16 moles), and 1-hydroxybenzotriazole (22g, 0.16 moles). Stir at room temperature over the weekend; thenconcentrate in vacuo to an orange oil. Partition the oil between 2Nhydrochloric acid and ethyl acetate; separate aqueous layer and extractwith a second portion of ethyl acetate. Combine organic extracts,concentrate in vacuo, and wash with 10% aqueous potassium carbonate. Dryorganic layer over magnesium sulfate, filter and concentrate in vacuo toyield 64 g (95%) of the desired dipeptide as an oily residue. Dissolvethe crude dipeptide in 150 mL of trifluoroacetic acid, stir at roomtemperature for 1 h; then remove the solvent in vacuo. Take up theresulting residue on 800 mL of commercial 2N ammonia in methanolsolution, and stir at room temperature overnight. Heat the mixture at70° C. for several hours; then cool to room temperature and remove thesolvent in vacuo. Redissolve the residue in dichloromethane, filter offthe resulting precipitate, and concentrate the filtrate in vacuo. Applythe residue to a silica gel column. Elute with a 2% mixture of 2Nammonia-methanol in dichloromethane to obtain 31.9 g (72%) ofS-(4-benzyl-3,6-dioxopiperazin-2-yl)acetic acid methyl as a yellow oil.

To a 0° C. solution of S-(4-benzyl-3,6-dioxopiperazin-2-yl)acetic acidmethyl ester (31.9 g, 0.12 moles) in tetrahydrofuran (1 L), add lithiumaluminum hydride via slow cannulation (350 mL of a commercial 1.0 Msolution in tetrahydrofuran). Stir at room temperature overnight, quenchby successive careful addition of 13.3 mL of water, 13.3 mL of 15%aqueous sodium hydroxide, and 39.9 mL of water, all the while withvigourous stirring to ensure formation of a fine precipitate. Filterthrough a fritted funnel, washing the solids well with tetrahydrofuranand dichloromethane. Concentrate in vacuo to provide 26.5 g of an oilyresidue, apply directly to a silica gel column. Elute with a 5% mixtureof 7N ammonia-methanol in dichloromethane, to obtain the desired productas an orange oil which solidifies under vacuum. Take up the solid inacetonitrile and sonicate for a few minutes. Filter the resultingprecipitate to obtain 7.5 g (25%) ofS-(−)-2-(4-benzylpiperazin-2-yl)ethanol as an off-white crystallinesolid, mp 78.9-80.4° C. Concentrate the mother liquor to obtain 6.8 g(23%) of slightly less pure material as an amorphous solid

Combine (S)-2-(4-benzylpiperazin-2-yl)ethanol (3.08 g, 14.0 mmol) inmethylenechloride (30 mL) and di-tert-butyl dicarbonate (3.2 g, 14.7mmol) in 5 mL CH₂Cl₂ and add dropwise at room temperature. After 1 hour,quench the reaction mixture by adding water, extract with CH₂Cl₂, washwith water and brine, and dry over Na₂SO₄. Purification by silica gelchromatography of the crude product by using MeOH/CH₂Cl₂ (5% to 10%) asthe eluent, gives 3.17 g (Yield 71%) of title compound: ¹H NMR (400 MHz,CDCl₃): δ7.37-7.23 (m, 5H), 4.27-4.10 (m, 1H), 4.02-3.80 (m, 211),3.61-3.23 (m, 4H), 3.00 (t, 1H, J=10 Hz), 2.71-2.56 (m, 2H), 2.24-2.22(m, 2H), 2.01 (dt, 1H, J=3.4, 12.2 Hz), 1.46 (s, 9H).

Example 197 (S)-4-Benzyl-2-(2-oxo-ethyl)-piperazine-1-carboxylic acidtert-butyl ester

Add dichloromethane (3 mL) to a 50 mL dry schlenk flask, followed byoxalyl chloride (0.178 g, 1.4 mmol) and cool the solution to −78° C. andtreat with dimethyl sulfoxide (0.171 g, 2.2 mmol) and triethylamine(0.505 g, 5.0 mmol). After 10 min, add a solution of(S)-4-benzyl-2-(2-hydroxy-ethyl)-piperazine-1-carboxylic acid tert-butylester (0.320 g, 1.0 mmol) in dichloromethane (5 mL) and stir theresulting mixture at −78° C. for 1 hour. Quench the reaction mixture byadding sat. NaHCO₃, extract the aqueous solution with CH₂Cl₂, wash theorganic solvent with brine, and dry over Na₂SO₄. Purification by silicagel chromatography of the crude product using MeOH/CH₂Cl₂ (5% to 10%) aseluent to give the title compound (160 g, 50%) as a light yellow oil:mass spectrum (Electrospray): m/z=319.2 (M+1); ¹H NMR (400 MHz, CDCl₃):δ9.74 (t, 1H, J=2.0 Hz), 7.33-7.21 (m, 5H), 4.57 (br, 1H), 3.88 (m, 2H),33.52-3.40 (m, 21H), 3.15-3.05 (m, 1H), 2.83-2.66 (m, 4H), 2.22-2.18 (m,1H), 2.03 (dt, 1H, J=3.4, 11.8 Hz), 1.44 (s, 9H).

Example 198 (S)-4-Benzyl-2-(3-phenyl-allyl)-piperazine-1-carboxylic acidtert-butyl ester

Combine and cool to 0° C. a solution of(S)-4-benzyl-2-(2-oxo-ethyl)-piperazine-1-carboxylic acid tert-butylester (1.95 g, 6.13 mmol) and diethyl benzyl phosphonate (4.23 g, 18.55mmol) in dry DMF (25 mL), and add solid sodium methoxide (95%, 1.15 g,21.3 mmol) in a single portion, and stir at 0° C. for 30 minutes. Dilutethe mixture with CH₂Cl₂, wash with brine and dry the organic layer overNa₂SO₄. Purification by silica gel chromatography of the crude productusing EtOAC/CH₂Cl₂ (2% to 10%) as eluent gives the title compound (2.37g) as a white solid: mass spectrum (Electrospray): m/z=393.3 (M+1); ¹HNMR (400 MHz, CDCl₃): δ7.37-7.21 (m, 10H), 6.34-6.30 (m, 1H), 6.12-6.02(m, 1H), 4.10 (br, 1H), 3.87 (br, 1H), 3.59-3.52 (m, 1H), 3.41-3.35 (m,1H), 3.13 (m, 1H), 2.82-2.59 (m, 4H), 2.18-2.04 (m, 2H), 1.39 (s, 9H).

Example 199 (S)-1-Benzyl-3-(3-phenyl-allyl)-piperazine

Dissolve (S)-4-benzyl-2-(3-phenyl-allyl)-piperazine-1-carboxylic acidtert-butyl ester (2.37 g, 6.04 mmol) in toluene (50 mL) and treat withtrifluoroacetic acid (10.3 g, 90.5 mmol) at room temperature, and stirthe reaction mixture. After overnight, dilute the reaction with CH₂Cl₂,and basify with 2N NaOH (50 mL), extract the aqueous solution withCH₂Cl₂, wash the combined organic layers brine, dry over Na₂SO₄. Passthe crude product through a SCX column (10 g), collect the 0.2N NH₃/MeOHeluent and concentrate to give 1.46 g of the title compound: massspectrum (Electrospray): m/z=293.3 (M+1). ¹H NMR (400 MHz, CDCl₃):δ7.35-7.19 (m, 10H), 6.54-6.47 (m, 1H) 6.18-6.11, 5.70-5.60 (m, 1H),3.70 (s, 2H), 2.97-2.73 (m, 5H), 2.40-2.18 (m, 2H), 2.09-2.00 (m, 1H),1.83 (t, 1H, J=9.8 Hz).

Example 200 (S)-2-(3-Phenyl-propyl)-piperazine

Combine (S)-1-benzyl-3-(3-phenyl-allyl)-piperazine (1.45 g, 5.0 mmol),10% Pd/C (265 mg, 0.025 mmol) and ammonia formate (1.57 g, 25.0 mmol) inEtOH (90 mL) and heat to reflux for 3 hours, cool to room temperature,remove the catalyst by filtration. Concentrate the solvent to a residue,which ¹H NMR shows that the carbon-carbon double bond has been reduced,but the benzyl group remains. Subject the residue to the reaction with10% Pd(OH)₂/C (350 mg, 0.5 mmol) in EtOH with a balloon of hydrogenunder reflux conditions. After refluxing for 3 hours, cool the reactionto room temperature, remove the catalyst, concentrate to a residue, andpurification by silica gel chromatography using 2N NH₃ in MeOH anddichloromethane (5%-15%) to give the title compound (950 mg, 93%): massspectrum (Electrospray): m/z=205.2 (M+1); ¹H NMR (CDCl₃): δ7.29-7.15 (m,5H), 2.97-2.59 (m, 6H), 2.35 (t, 1H, J=9.8 Hz), 1.70-1.45 (m, 6H),1.38-1.25 (m, 2H).

Example 201(S)-2-Methyl-10-(3-(3-phenyl-propyl)-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene,dihydrochloric acid

Combine (S)-2-(3-phenyl-propyl)-piperazine (510 mg, 2.50 mmol),2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine (663 mg, 2.50mmol), diisopropylethylamine (4 mL), DMSO/Toluent (1.25/2.5 mL), heat at110° C. After 24 hours, cool to ambient temperature, remove the solvent,dilute with CH₂Cl₂, wash with water, brine, and dry over with Na₂SO₄.Purification by silica gel chromatography of the crude product using 2Nammonia in methanol-methylene chloride (2-4%) as the eluent gives 310 mgbrown foam of the free base: mass spectrum (Electrospray): m/z=417.3(M+1). ¹H NMR (400 MHz, CDCl₃): δ7.31-7.23 (m, 2H), 7.20-7.15 (m, 3H),7.04-6.85 (m, 3H), 6.60 (dd, 1H, J=1.5, J=7.8 Hz), 6.28 (d, 1H, J=1.5Hz), 4.94 (s, 1H), 4.07-3.96 (m, 2H), 3.05-2.89 (m, 3H), 2.79-2.77 (m,1H), 2.64 (t, 2H, J=7.3 Hz), 2.57-2.51 (m, 1H), 2.29 (d, 3H, J=1.0 Hz),1.76-1.40 (m, 5H). Treat the free base with NH₄Cl (2.0 eq.) in MeOH,remove the solvent, dissolve in CH₃CN/H₂O=50/50, lyophilize overnight togive the title compound as a yellow solid: mass spectrum (Electrospray):m/z=417.1 (M+1-2HCl), 416.1 (M−1-2HCl).

Example 202(S)-2-Methyl-10-(3-(3-phenyl-propyl)-4-methyl-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene,dihydrochloricacid

Combine(S)-2-methyl-10-3-(3-phenyl-propyl)-piperazin-1-yl]-4H-3-thia-4,9-diaza-benzo[f]azulene(320 mg, 0.77 mmol), formaldehyde (37% aq, 68.6 mg, 0.85 mmol) andsodium triacetoxyborohydride (244.7 mg, 1.15 mmol) in 1,2-dichloroethane(15 mL) and stir at room temperature. After 4 hours, quench the reactionadding sat. NaHCO₃, extract the aqueous solution with CH₂Cl₂ (3×10 mL),wash the organic solvent with brine, and dry over Na₂SO₄. Concentratethe solvent in vaccuo to give a residue and purify by silica gelchromatography using 2N ammonia in methanol-methylene chloride (2-4%) asthe eluent to give 285 mg (yield 86%) light brown foam of the free base:mass spectrum (Electrospray): m/z=431.3 (M+1); ¹H NMR (400 MHz, CDCl₃):δ7.29-7.16 (m, 5 H), 7.03-6.85 (m, 3 H), 6.59 (dd, 1H, J=1.5, J=7.8 Hz),6.28 (d, 1H, J=1.0 Hz), 4.94 (s, 1H), 3.99-3.89 (m, 2H), 3.14-3.09 (m,1H), 2.85-2.77 (m, 2H), 2.68-2.56 (m, 2H), 2.35-2.14 (m, 8H), 1.74-1.42(m, 4H). Analysis calculated for C₂₆H₃₀N₄S.0.3H₂O: C, 71.62; H, 7.07; N,12.86. Found: C, 71.69; H, 6.94; N, 12.48. Treat the free base withammonia chloride (2.0 eq.) in MeOH at 45° C. for 1 hour, remove thesolvent, dissolve in a mix solvent (15 mL) CH₃CN/H₂O=50/50, lyophilizeovernight to give the title compound as a yellow solid.

By a method similar to Example 59, using the appropriate startingmaterials, the following compounds were prepared and isolated as the (S)isomer except where noted below:

No: ArAlk Data 209 CH₂(4-Br)Ph mp 97-112° C.: ¹H NMR(CDCl₃): δ2.26(s,3H), 2.59(dd, 1H), 2.65(dd, 1H), 2.74(dd, 1H), 2.88-2.80(m, 1H),3.03-2.91(m, 3H), 3.99(d, 1H), 4.07(d, 1H), 4.97(s, 1H), 6.17(t, 1H),6.59(dt, 1H), 6.87(ddd, 1H), 6.97(ddd, 1H), 7.11(d, 2H), 7.43(d, 2H);MS(APCI)m/z(rel intensity)468.3(96), 469.3(100). 57% yield. 210CH₂(4-I)Ph mp 105-121° C.: ¹H NMR(CDCl₃): δ2.26(s, 3H), 2.58(dd, 1H),2.66(dd, 1H), 2.73(dd, 1H), 2.88-2.80(m, 1H), 3.03-2.91(m, 3H), 3.99(d,1H), 4.07(d, 1H), 4.97(s, 1H), 6.17(d, 1H), 6.60(dd, 1H), 6.87(dt, 1H),7.03-6.94(m, 4H), 7.63(d, 2H); MS(APCI)m/z(rel intensity)515.4(100). 47%yield. 211 CH₂(4-O—CH₂CH₂═CH₂)Ph ¹H NMR(CD₃OH): δ2.17(bs, 3H), 2.87(m,1H), 3.05(m, 1H), 3.39-3.50(m, 2H), 3.63-3.86(m, 3H), 4.07(m, 1H),4.29(m, 1H), 4.55(m, 2H), 5.26(m, 1H), 5.40(m, 1H), 6.07(m, 1H),6.25(bs, 1H), 6.88(d, 1H), 6.95(d, 2H), 7.12-7.28(m, 5H);MS(APCI)m/z(rel intensity)445(100). 10 mg product. 212CH₂(thiophen-3-yl) mp 82-94° C.: ¹H NMR(CDCl₃): δ2.28(s, 3H), 2.67(dd,1H), 2.70(dd, 1H), 2.81(dd, 1H), 2.87(dd, 1H), 3.06-2.93(m, 3H), 3.99(d,1H), 4.11(d, 1H), 4.98(s, 1H), 6.23(d, 1H), 6.60(dd, 1H), 6.87(dt, 1H),6.97(dt, 1H), 6.99(dd, 1H), 7.02(dd, 1H), 7.05(m, 1H), 7.29(dd, 1H);MS(APCI)m/z(rel intensity 395.4(100). 47% yield. 213 CH₂(4-OiPr)Ph mp106-119° C.: ¹H NMR(CDCl₃): δ1.32(d, 3H), 1.34(d, 3H), 2.26(d, 3H),2.55(dd, 1H), 2.67(dd, 1H), 2.73(dd, 1H), 2.84(dd, 1H), 3.04-2.92(m,3H), 4.00(d, 1H), 4.09(d, 1H), 4.51(qt, 1H), 4.94(s, 1H), 6.21(d, 1H),6.60(dd, 1H), 6.84- 6.80(m, 2H), 6.87(dt, 1H), 6.96(dt, 1H), 7.01(dd,1H), 7.14- 7.10(m, 2H); MS(APCI)m/z(rel intensity)447.5(100). 44% yield.

By a method similar to Example 1, using the appropriate startingmaterials, the following compounds were prepared and isolated as the(S)isomer except where noted below:

No.: ArAlk Data 214 CH₂(4-Br)Ph ¹H NMR(DMSO-d₆): δ2.87(dd, 1H), 3.01(d,1H), 3.07(dd, 1H), 3.46(d, 1H), 4.08(m, 1H), 7.13(d, 2H), 7.48(d, 2H),7.94(s, 1H), 8.17(s, 1H); MS(APCI)m/z (rel intensity)283(100). 285(100).215 CH₂(4-I)Ph ¹H NMR(DMSO-d₆): δ2.84(dd, 1H), 2.97(d, 1H), 3.04(dd,1H), 3.45(d, 1H), 4.06(m, 1H), 6.99(d, 2H), 7.64(2H, 1H), 7.93(s, 1H),8.16(s, 1H); MS(APCI)m/z (rel intensity)331(100). 216 CH₂(thiophen-3-yl)mp 248-249° C.: ¹H NMR(DMSO-d₆): δ2.87(dd, 1H), 2.92(d, 1H), 3.09(dd,1H), 3.42(dd, 1H), 4.01(m, 1H), 6.88(dd, 1H), 7.12(m, 1H), 7.42(m, 1H),7.87(s, 1H), 8.10(s, 1H). 217 CH₂(4-iPrO)Ph mp 242° C.: ¹ HNMR(DMSO-d₆): δ1.24(d, 6H), 2.74(d, 1H), 2.80(dd, 1H), 3.03(dd, 1H),3.34(d, 1H), 4.02(m, 1H), 4.57(septet, 1H), 6.81(d, 1H), 7.04(d, 1H),7.87(s, 1H), 8.12(s, 1H). 217a CH₂(3,4-OCH₂O—)Ph mp 255-257° C.: ¹HNMR(DMSO-d₆) δ2.80(dd, 1H), 3.01(dd, 2H), 3.43(dd, 1H), 4.01(m, 1H),5.98(s, 2H), 6.63(dd, 1H), 6.70(s, 1H), 6.83(d, 1H), 7.92(s, 1H),8.09(d, 1H). 217b CH₂(3,4-Di-OCH₃)Ph mp 254-255° C.: ¹H NMR(DMSO-d₆)δ2.72(d, 1H), 2.78(dd, 1H), 2.98(dd, 1H), 3.33(dd, 1H), 3.65(s, 3H),3.67(s, 3H), 3.99(m, 1H), 6.63(d, 1H), 6.71(s, 1H), 6.81(d, 1H), 7.82(s,1H), 8.06(d, 1H).

By a method similar to Example 90, using the appropriate startingmaterials, the following compounds were prepared and isolated as thefree base and as the (S) isomer except where noted:

No: ArAlk Data 218 CH₂(4-Br)Ph mp 68-79° C.: ¹H NMR(CDCl₃): δ2.17(s,3H), 2.46-2.34(m, 3H), 2.48(s, 3H), 2.78(dd, 1H), 2.90(dt, 1H), 3.11(dd,1H), 3.19(ddd, 1H), 3.56(d, 1H), 3.96(d, 1H), 4.91(s, 1H), 5.96(s, 1H),6.57(dd, 1H), 6.85(ddd, 1H), 6.98-6.91(m, 2H), 7.06-7.02(m, 2H),7.41-7.36(m, 2H); MS(APCI)m/z(rel intensity)482.3 (96), 483.3(100). 92%yield. 219 CH₂(thiophen-3-yl) mp 58-72° C.: ¹H NMR(CDCl₃): δ2.20(s, 3H),2.48-2.37(m, 2H), 2.46(s, 3H), 2.58(dd, 1H), 2.78(dd, 1H), 2.89(dt, 1H),3.11(dd, 1H), 3.19(ddd, 1H), 3.69(d, 1H), 3.97(d, 1H), 4.92(s, 1H),6.06(s, 1H), 6.57(dd, 1H), 6.85(ddd, 1H), 7.00-6.92(m, 4H), 6.25(dd,1H); MS(APCI)m/z(rel intensity)409.3(100). 95% yield. 220 CH₂(4-I)Ph mp76-94° C.: ¹H NMR(CDCl₃): δ2.18(s, 3H), 2.46-2.36(m, 3H), 2.47(s, 3H),2.78(dd, 1H), 2.90(dt, 1H), 3.09(d, 1H), 3.20(ddd, 1H), 3.56(d, 1H),3.96(d, 1H), 4.91(s, 1H), 5.97(s, 1H), 6.57(dd, 1H), 6.85(ddd, 1H),6.97-6.89(m, 4H), 7.60-7.56(m, 2H); MS(APCI)m/z(relintensity)529.3(100). 87% yield. 221 CH₂(4-OiPr)Ph mp 92-98° C.: ¹HNMR(CDCl₃): δ1.32(d, 3H), 1.33(d, 3H), 2.14(s, 3H), 2.39-2.32(m, 2H),2.42(dd, 1H), 2.48(s, 3H), 2.77(dd, 1H), 2.91(dt, 1H), 3.10(d, 1H),3.18(dd, 1H), 3.62(d, 1H), 3.98(d, 1H), 4.49(qt, 1H), 4.89(s, 1H),5.99(s, 1H), 6.56(d, 1H), 6.81-6.76(m, 2H), 6.84(dd, 1H), 6.93(d, 2H),7.04(d, 2H); MS(APCI)m/z(rel intensity)461.5(100). 96% yield.

By a method similar to Example 58, using the appropriate startingmaterials, the following piperazine were prepared and isolated.

No: ArAlk Data 222 CH₂(4-I)Ph ¹H NMR(CDCl₃): δ2.52-2.60(m, 2H), 2.69(dd,1H), 2.81-2.93(m, 2H), 2.99-3.10(m, 4H), 6.95(d, 2H), 7.63(d, 2H);MS(APCI)m/z(rel intensity)303(100).

Example 2233-(S)-(4-(3-Methyl-but-2-enyloxy)-benzyl-piperazine-2,5-dione

To a suspension of 3-(S)-(4-hydroxy-benzyl)-piperazine-2,5-dione (15 g,68.2 mmol), cesium carbonate (111 g, 340 mmol), and tetrabutylammoniumiodide (1.25 g, 3.4 mmol) in anhydrous DMF. (500 mL), add at once, atambient temperature, 1-bromo-3-methyl-but-2-ene (51 g, 340 mmol). Stir12 hours then add water (300 mL). Concentrate to dryness then add water(500 mL) and extract with a dichloromethane/isopropyl alcohol (3/1)mixture. Wash the organic phases with 10% aqueous potassium carbonateand water then dry over magnesium sulfate. Evaporate the solvent, thentriturate the resulting solid with chloroform. Filter and dry to yield(14.3 g, 73%) of the title compound as a white solid: mp 217-220° C.: ¹HNMR (DMSO-d₆): δ 1.69 (s, 3H), 1.74 (s, 3H), 2.84-2.76 (m, 2H), 3.02(dd, 1H), 3.36 (dd, 1), 4.01 (m, 1H), 4.48 (d, 2H), 5.41 (m, 1H), 6.84(d, 2H), 7.05 (d, 2H), 7.86 (s, 1H), 8.12 (d, 1H).

By a method similar to Example 223, using the appropriate startingmaterials, the following compounds were prepared and isolated.

No: ArAlk Data 224 CH₂(4-OCH₂CH═CH₂)Ph mp 258° C.: ¹H NMR(DMSO-d₆):δ2.78(d, 1H), 2.81(dd, 1H), 3.03(dd, 1H), 3.35(dd, 1H), 4.01(m, 1H),4.53(d, 2H), 5.24(dd, 1H), 5.38(dd, 1H), 6.07-5.96(m, 1H), 6.86(d, 2H),7.06(d, 2H), 7.87(s, 1H), 8.11(d, 1H). 224a CH₂-(4-OCH₂C(═CH₂)CH₃Ph mp248-249° C.: ¹H NMR(DMSO-d₆) δ1.75(s, 3H), 2.78(d, 1H), 2.81(dd, 1H),3.03(dd, 1H), 3.35(dd, 1H), 4.01(m, 1H), 4.43(s, 2H), 4.94(s, 1H),5.04(s, 1H), 6.86(d, 2H), 7.06(d, 2H), 7.87(s, 1H), 8.11(d, 1H).

By a method similar to Example 24, using the appropriate startingmaterials, the following piperazines were prepared and isolated wereprepared and isolated as the (S) isomer except where noted below.

No: ArAlk Data 225 CH₂(4-O—CH₂CH═CH₂)Ph mp 89-90° C.: ¹H NMR(CDCl₃):δ2.45(dd, 1H), 2.48(dd, 1H), 2.63(dd, 1H), 2.82-2.67(m, 3H), 2.90(dd,2H), 2.96(dd, 1H), 4.51(t, 1H), 4.52(t, 1H), 5.28(dq, 1H), 5.41(dq, 1H),6.11-6.00(m, 1H), 6.86(d, 2H), 7.11(d, 2H); MS (APCI)m/z(relintensity)233.3(100). 226 CH₂(thiophen-3-yl) mp 75-77° C.: ¹HNMR(CDCl₃): δ2.48(dd, 1H), 2.59(dd, 1H), 2.95-2.66(m, 6H), 2.98(dd, 1H),6.95(dd, 1H), 7.02(m, 1H), 7.28(m, 1H); MS(APCI)m/z(rel intensity)183.2(100). 227 CH₂(4-OiPr)Ph ¹H NMR(CDCl₃)δ1.31(s, 3H), 1.33(s, 3H),2.45(dd, 1H), 2.48(dd, 1H), 2.63(dd, 1H), 2.82-2.67(m, 3H), 2.90(dd,2H), 2.96(dd, 1H), 4.45(qt, 1H), 6.81(d, 2H), 7.15(d, 2H);MS(APCI)m/z(rel intensity)235.3(100). 228 CH₂(4-OPh)Ph ¹HNMR(CDCl₃)δ2.48(dd, 1H), 2.52(dd, 1H), 2.67(dd, 1H), 2.70-2.96(m, 5H),2.98(dd, 1H), 6.95(d, 2H), 7.01(d, 2H), 7.10(t, 1H), 7.16(d, 2H),7.32(t, 2H); MS(APCI)m/z (rel intensity)269(100). 229 CH₂(4-i-Pr)Ph ¹HNMR(CDCl₃)δ1.24(d, 6H), 2.47(dd, 1H), 2.50(dd, 1H), 2.63-2.92(m, 7H),2.96(dd, 1H), 7.09-7.17(m, 4H); MS(APCI)m/z(rel intensity)219(100). 230CH₂(3,5-DiCH₃)Ph ¹H NMR(CDCl₃)δ2.28(s, 6H), 2.43(dd, 1H), 2.49(dd, 1H),2.62(dd, 1H), 2.66-2.99(m, 6H), 6.82(s, 2H), 6.86(s, 1H);MS(APCI)m/z(rel intensity)205(100). 231 CH₂(3,4-OCH₂O—)Ph mp 80-84° C.;¹H NMR(CDCl₃)δ2.40(dd, 1H), 2.70(dd, 1H), 2.61(dd, 1H), 2.82-2.71(m,3H), 2.99-2.87(m, 3H), 5.93(s, 2H), 6.76-6.62(m, 3H); MS(APCI)m/z(relintensity)221.3(100). 232 CH₂(4-O—CH₂CH═C(CH₃)₂)Ph mp 43-47° C.: ¹HNMR(CDCl₃)δ1.77(s, 3H), 1.89(s, 3H), 2.45(dd, 1H), 2.48(dd, 1H),2.63(dd, 1H), 2.82-2.67(m, 3H), 2.90(dd, 2H), 2.96(dd, 1H), 4.48(s, 2H),5.49(ddd, 1H), 6.85(d, 2H), 7.10(d, 2H); MS(APCI)m/z(relintensity)261.5(100). 233 CH₂(4-O—CH₂C(═CH₂)CH₃)Ph mp 73-75° C.: ¹HNMR(CDCl₃)δ1.83(s, 3H), 2.45(dd, 1H), 2.48(dd, 1H), 2.63(dd, 1H),2.82-2.67(m, 3H), 2.90 (dd, 2H), 2.96(dd, 1H), 4.41(s, 2H), 4.98(s, 1H),5.09(s, 1H), 6.85(d, 2H), 7.09(d, 2H); MS(APCI)m/z(relintensity)247.4(100). 234 CH₂(3,4-DiO—CH₃)Ph ¹H NMR(CDCl₃)δ2.45(dd, 1H),2.50(dd, 1H), 2.65(dd, 1H), 2.82-2.71(m, 3H), 2.96-2.87(m, 2H), 2.98(dd,1H), 3.86(s, 3H), 3.87(s, 3H), 6.83-6.72(m, 3H); MS(APCI)m/z (relintensity)237.3(100). 235 CH₂(2-OCH₂CH₃)Ph ¹H NMR(CDCl₃)δ1.43(t, 3H),2.45-2.53(m, 2H), 2.71- 2.79(m, 3H), 2.86-2.95(m, 4H), 4.03(q, 2H),6.82-6.87(m, 2H), 7.12-7.28(m, 2H); MS(APCI)m/z(rel intensity)221 (100).235a CH₂(3-OPh)Ph ¹H NMR(CDCl₃)δ2.47(dd, 1H), 2.49(dd, 1H), 2.64(dd,1H), 2.67-2.96(m, 6H), 6.86(d, 1H), 6.88(s, 1H), 6.93(d, 1H), 7.01(d,2H), 7.10(t, 1H), 7.24(t, 1H), 7.33(t, 2H); MS (APCI)m/z(relintensity)269(100). 235b CH₂(2,4-Di-OCH₃)Ph ¹H NMR(CDCl₃)δ2.43(dd, 1H),2.47(dd, 1H), 2.66(dd, 1H), 2.69-2.96(m, 6H), 3.78(s, 3H), 3.79(s, 3H),6.41(d, 1H), 6.44(s, 1H), 7.03(d, 1H); MS(APCI)m/z(relintensity)237(100).

By a method similar to Example 59, using the appropriate startingmaterials, the following compounds were prepared and isolated as the (S)isomer except where noted below:

No: ArAlk Data 236 CH₂(3,5-DiCH₃)Ph ¹H NMR(CDCl₃)δ2.27(s, 3H), 2.29(s,6H), 2.51(dd, 1H), 2.69(dd, 1H), 2.74(dd, 1H), 2.82(ddd, 1H),2.93-3.02(m, 3H), 3.99(m, 1H), 4.12(m, 1H), 4.96(s, 1H), 6.23(s, 1H),6.60(d, 1H), 6.85(s, 2H), 6.86(s, 1H), 6.86(t, 1H), 6.96(t, 1H), 7.02(d,1H); MS(APCI)m/z(rel intensity)417(100). 35% yield. 237CH₂(4-O—CH₂C(═CH₂)CH₃)Ph mp 106-113° C.; ¹H NMR(CDCl₃)δ1.83(s, 3H),2.26(s, 3H), 2.56(dd, 1H), 2.66(dd, 1H), 2.73(dd, 1H), 2.84(dd, 1H),3.04-2.92(m, 3H), 4.00(d, 1H), 4.08(d, 1H), 4.41(s, 2H), 4.95(s, 1H),4.99(m, 1H), 5.09(m, 1H), 6.20(d, 1H), 6.60(dd, 1H), 6.89-6.84(m, 3H),6.96(dt, 1H), 7.02(dd, 1H), 7.15-7.01(m, 2H); MS(APCI)m/z(relintensity)459.5 (100). 41% yield. 238 CH₂(2-OCH₂CH₃)Ph ¹HNMR(CDCl₃)δ1.42(t, 3H), 2.22(s, 3H), 2.62(dd, 1H), 2.68(dd, 1H),2.83-2.90(m, 2H), 2.97(ddd, 1H), 3.02-3.11(m, 2H), 3.97(m, 1H), 4.02(q,2H), 4.03(m, 1H), 4.99(s, 1H), 6.18(s, 1H), 6.59(d, 1H), 6.82-6.89(m,3H), 6.95(t, 1H), 7.01(d, 1H), 7.16-7.21(m, 2H); MS(APCI)m/z(relintensity)433(100). 50 mg of product. 239 CH₂(2-O-i-Pr)Ph ¹HNMR(CDCl₃)δ1.33(dd, 6H), 2.22(s, 3H), 2.55(m, 1H), 2.65(m, 1H),2.81-3.20(m, 5H), 3.92(d, 1H), 4.07(d, 1H), 4.51(m, 1H), 4.91(s, 1H),6.16(s, 1H), 6.58(d, 1H), 6.85(m, 3H), 6.95(t, 1H), 6.99(d, 1H), 7.15(d,2H); MS(ESI) m/z(rel intensity)447(100). 1.0 g of product. 240CH₂(pyridin-2-yl) mp 115-117° C.(decomp); ¹H NMR(CDCl₃)δ2.25(s, 3H),2.90-2.96(m, 4H), 3.10-3.20(m, 2H), 3.40(m, 1H), 4.05(m, 2H), 5.09(bs,1H), 6.22(s, 1H), 6.60(d, 1H), 6.85(t, 1H), 6.96(t, 1H), 6.99(d, 1H),7.12-7.20(m, 2H), 7.60(t, 1H), 8.52(d, 1H); MS(es)m/z(relintensity)390(100). 50 mg of product. 240a CH₂(3-OPh)Ph mp 97-103° C.;¹H NMR(CDCl₃)δ2.26(s, 3H), 2.62(dd, 1H), 2.65(dd, 1H), 2.75(dd, 1H),2.86(dd, 1H), 2.94(dd, 1H), 3.05-2.97(m, 2H), 3.99(d, 1H), 4.06(d, 1H),4.94(s, 1H), 6.20(s, 1H), 6.59(dd, 1H), 6.90-6.84(m, 3H), 7.04- 6.93(m,5H), 7.11(ddd, 1H), 7.27(t, 1H), 7.36-7.31(m, 2H); MS(APCI)m/z(relintensity)481.5(100). 43% yield.

By a method similar to Example 90, using the appropriate startingmaterials, the following compounds were prepared and isolated as thefree base and as the (S) isomer except where noted:

No: ArAlk Data 241 CH₂(4-O—CH₂CH═C(CH₃)₂)Ph mp 74-78° C.; ¹ HNMR(CDCl₃)δ1.75(s, 3H), 1.81(s, 3H), 2.13(s, 3H), 2.39-2.32(m, 2H),2.42(dd, 1H), 2.48(s, 3H), 2.76(dd, 1H), 2.91(dt, 1H), 3.11(d, 1H),3.18(dd, 1H), 3.61(d, 1H), 3.99(d, 1H), 4.47(d, 2H), 4.91(s, 1H),5.50(m, 1H), 5.97(bs, 1H), 6.56(dd, 1H), 6.87-6.79(m, 3H), 6.95- 6.91(m,2H), 7.05(d, 2H); MS(APCI)m/z(rel intensity) 487.5(100). 93% yield. 242CH₂(3,4-OCH₂O—)Ph mp 105-108° C.; ¹H NMR(CDCl₃)δ2.18(d, 3H), 2.39-2.32(m, 2H), 2.43(dd, 1H), 2.47(s, 3H), 2.78(dd, 1H), 2.90(dt, 1H), 3.08(d,1H), 3.20(dd, 1H), 3.61(d, 1H), 3.97(d, 1H), 4.91(s, 1H), 5.92(dd, 2H),6.02(bs, 1H), 6.57(dd, 1H), 6.60(dd, 1H), 6.72-6.66(m, 2H), 6.85(ddd,1H), 6.96-6.92(m, 2H); MS(APCI)m/z(rel intensity)447.4(100). 90% yield.243 CH₂(3,4-di-OCH₃)Ph mp 103-108° C.; ¹H NMR(CDCl₃)δ2.13(s, 3H),2.39-2.32(m, 2H), 2.43(dd, 1H), 2.49(s, 3H), 2.76(dd, 1H), 2.91(dt, 1H),3.15-3.08(m, 1H), 3.18(dd, 1H), 3.67(d, 1H), 3.83(s, 3H), 3.86(s, 3H),4.00(d, 1H), 4.91(s, 1H), 5.96(bs, 1H), 6.57(dd, 1H), 6.65(d, 1H),6.70(dd, 1H), 6.77(d, 1H), 6.85(ddd, 1H), 6.95-6.91(m, 2H);MS(APCI)m/z(rel intensity) 463.4(100). 90% yield. 244CH₂(4-O—CH₂C(═CH₂)CH₃)Ph mp 93-100° C.; ¹H NMR(CDCl₃)δ1.83(s, 3H),2.14(s, 3H), 2.44-2.32(m, 3H), 2.48(s, 3H), 2.76(dd, 1H), 2.91(dt, 1H),3.11(d, 1H), 3.18(dd, 1H), 3.61(d, 1H), 3.98(d, 1H), 4.40(s, 2H),4.90(s, 1H), 4.99(m, 1H), 5.09(m, 1H), 5.98 (bs, 1H), 6.56(dd, 1H),6.87-6.79(m, 3H), 6.95-6.91(m, 2H), 7.05(d, 2H); MS(APCI)m/z(relintensity)473.5(100). 94% yield. 245 CH₂(4-iPr—Ph) mp 94-99° C.; ¹HNMR(CDCl₃)δ1.23(d, 3H), 1.25(d, 3H), 2.16(s, 3H), 2.46-2.38(m, 3H),2.49(s, 3H), 2.93-2.79(m, 3H), 3.12(d, 1H), 3.22(dd, 1H), 3.6(d, 1H),3.92(d, 1H), 4.91(s, 1H), 6.07(bs, 1H), 6.84(ddd, 1H), 6.96-6.88(m, 2H),7.16-6.04(m, 5H); MS(APCI)m/z(rel intensity)445.6 (100). 77% yield. 246CH₂(3,5-DiCH₃)Ph mp 96-103° C.; ¹H NMR(CDCl₃)δ2.10(s, 3H), 2.25(s, 6H),2.48-2.32(m, 3H), 2.49(s, 3H), 2.87(dd, 1H), 2.91(dt, 1H), 3.10-3.05(m,1H), 3.26(dd, 1H), 3.62(d, 1H), 3.94(d, 1H), 5.00(m, 1H), 5.96(bs, 1H),6.56(d, 1H), 6.74(d, 2H), 6.81(s, 1H), 6.83(dd, 1H), 6.94-6.90(m, 2H);MS(APCI) mz/(rel intensity)431.5(100). 82% yield. 247 CH₂(2-OCH₂CH₃)Phmp 135-137° C.; ¹H NMR(CDCl₃)δ1.41(t, 3H), 2.10(s, 3H), 2.42(d, 3H),2.53(s, 3H), 2.86-2.95(m, 2H), 3.20(m, 2H), 3.61(d, 1H), 4.02(m, 3H),4.89(s, 1H), 5.96(s, 1H), 6.56(d, 1H), 6.84(m, 3H), 6.92(d, 2H), 7.08(d,1H), 7.15 (t, 1H); MS(ESI)m/z(rel intensity)447(100). 278 mg of product.248 CH₂(4-Ph)Ph ¹H NMR(CDCl₃)δ2.03(s, 3H), 2.42-2.53(m, 3H), 2.52(s,3H), 2.87(m, 1H), 2.95(ddd, 1H), 3.21(m, 2H), 3.63(m, 1H), 3.96(m, 1H),4.89(s, 1H), 6.01(s, 1H), 6.56(d, 1H), 6.84(m, 1H), 6.92(m, 2H), 7.25(d,2H), 7.34(t, 1H), 7.43(t, 2H), 7.50(d, 2H), 7.58(d, 2H); MS(APCI)m/z(relintensity)479(100). 421 mg of product. 249 CH₂(2-O—iPr)Ph mp 184-186°C.; ¹H NMR(CDCl₃)δ1.21(d, 3H), 1.35(d, 3H), 2.07(s, 3H), 2.41(m, 3H),2.53(s, 3H), 2.83-2.96(m, 2H), 3.19(m, 2H)3.59(d, 1H), 4.00(d, 1H),4.55(m, 1H), 4.87(s, 1H), 5.92(s, 1H), 6.55(d, 1H), 6.81(m, 3H), 6.92(d,2H), 7.08(d, 1H), 7.13(t, 1H); MS(ESI)m/z(rel intensity)461(100). 378 mgof product.

Example 255 1-Acetyl-3-(pydridin-3-yl)methylene-piperazine-2,5-dione

Add DMF (60 mL) to a mixture of 1,4-diacetyl-piperazine-2,5-dione (5.94g, 30 mmol) and 3-pyridinecarboxaldehyde (12.84 g, 120 mmol). Cool to 0°C. Add portionwise over 20 min a solution of potassium tert-butoxide(3.36 g, 30 mmol) in tert-butanol (60 mL) to this solution. Warm to roomtemperature and stir for 2 h. Pour the mixture into water (400 mL) andfilter. Wash with water three times, then with hexanes to obtain thetitle compound as a yellow powder (4.0 g, 54%): ¹H NMR (DMSO-d₆) δ 2.51(s, 3H), 4.37 (s, 2H), 6.95 (s, 1H), 7.43 (dd, 1H), 7.96 (d, 1H1), 8.50(d, 1H), 8.73 (s, 1H), 10.64 (bs, 1H).

By the method of example 255, the following compounds were prepared andisolated:

No: R Data 256 2-pyridyl ¹H NMR(DMSO-d₆)δ2.49(s, 3H), 4.32(s, 2H),6.85(s, 1H), 7.36(dd, 1H), 7.67(d, 1H), 7.90(t, 1H), 8.70(d, 1H),12.43(bs, 1H). 78% yield, 36 g. 257 (3,5-Di-OCH₃)Ph ¹HNMR(CDCl₃)δ2.61(s, 3H), 3.73(s, 6H), 4.56(s, 2H), 6.43(s, 1H), 6.45(s,2H), 7.06(s, 1H), 8.09(bs, 1H). 98% yield 17.8 g gave 26.8 g. 258(3,5-Di-CH₃)Ph mp 172-174° C.: ¹H NMR(CDCl₃)δ2.30(s, 6H), 2.61(s, 3H),4.46(s, 2H), 6.95(s, 2H), 6.98(s, 1H), 7.08(s, 1H), 7.99(bs, 1H). 64%yield, 17.8 g gave 15.8 g. 259 (2-OEt)Ph mp 142-145° C.: ¹HNMR(CDCl₃)δ1.48(t, 3H), 2.63(t, 3H), 4.17(q, 2H), 4.45(s, 2H), 6.96(d,1H), 7.01(t, 1H), 7.11(s, 1H), 7.30(d, 1H), 7.34(t, 1H), 8.80(bs, 1H).64% yield, from 17.8 g gave 16.5 g. 260 (4-OPh)Ph mp 165-167° C.: ¹HNMR(CDCl₃)δ2.62(s, 3H), 4.48(s, 2H), 7.01-7.03(m, 4H), 7.11(s, 1H),7.15(t, 1H), 7.33-7.38(m, 4H), 7.97(bs, 1H). 92% yield, 23.8 g gave 37.0g 261 (4-i-Pr)Ph mp 155-168° C.: ¹H NMR(CDCl₃)δ1.24(d, 6H), 2.62(s, 3H),2.90(septet, 1H), 4.48(s, 2H), 7.13(s, 1H), 7.27-7.31(m, 4H), 7.91(bs,1H). 83% yield, 23.8 g gave 32.7 g 262 (2-OiPr)Ph mp 187-192° C.; ¹HNMR(CDCl₃)δ1.41(d, 6H), 2.67(s, 3H), 4.47(s, 2H), 4.71(m, 1H), 7.00(m,2H), 7.11(s, 1H), 7.31(m, 2H). 263 (2,4-Di-OCH₃)Ph ¹HNMR(DMSO-d₆)δ2.42(s, 3H), 3.75(s, 3H), 3.78(s, 3H), 4.26(s, 2H), 6.54(d,1H), 6.55(s, 1H), 6.99(s, 1H), 7.49(d, 1H), 10.01(bs, 1H).

Example 266 (S)-1-Acetyl-3-(3-phenoxy-benzyl)-piperazine-2,5-dione

Add EtOH (60 mL) and DMF (15 mL) to the dehydrodiketopiperazine (15-50g). Exchange the atmosphere to nitrogen with a Parr shaker. Add acatalytic amount of Pd/C (DeGaussa type from Aldrich, 50% water, 100mg). Exchange the atmosphere three times with hydrogen to a pressure of30 psi. During the reaction, the mixture will form a solution (exceptfor the catalyst) and shake for an additional 30 minutes or until nomore hydrogen uptake is observed. Filter the catalyst through celite,and concentrate to dryness to obtain the title compound as a white solidSeparation of the S-isomers occurs via resolution of the piperazines. Inall other examples, only the ethanol was removed and the crude productwas used as is in a solution in DMF for treatment with hydrazine as inexample 267. ¹H NMR (CDCl₃) δ 2.54 (s, 3H), 3.11 (dd, 1H), 3.18 (dd,1H), 3.50 (d, 1H), 4.22 (d, 1H), 4.36 (m, 1H), 6.82 (s, 1H), 6.90-6.93(m, 2H), 6.96 (d, 2H), 7.12 (t, 1H), 7.18 (bs, 1H), 7.27 (t, 1H), 7.34(t, 2H).

Example 267 3-(3-Phenoxy-benzyl)-piperazine-2,5-dione

Add hydrazine hydrate (0.7 mL, 14.2 mmol) to a solution of1-acetyl-3-(3-phenoxy-benzyl)-piperazine-2,5-dione (4.8 g, 14.2 mmol) inDMF (10 mL). Stir 2 h, dilute with water (50 mL) and stir an additional30 minutes. Filter, wash with water, then cold methanol to obtain thetitle compound as a white powder (2.8 g, 67%): ¹H NMR (CDCl₃) δ 2.84(dd, 1H), 2.96 (d, 1H), 3.05 (dd, 1H), 3.42 (d, 1H), 4.03 (m, 1H),6.83-6.97 (m, 5H), 7.09 (t, 1H), 7.27 (t, 1H), 7.34 (t, 2H), 7.92 (bs,1H), 8.12 (s, 1H).

By the method of example 266 and 267, the following compounds wereprepared and isolated: Separation of the S-isomers occurs via resolutionof the piperazines with the use of tartartic acid.

No: R Data 269 (3,5-Di-OCH₃)Ph mp 212-213° C.: ¹H NMR(DMSO-d₆) δ2.76(dd,1H), 2.87(d, 1H), 2.93(dd, 1H), 3.34(d, 1H), 3.63(s, 6H), 3.99(m, 1H),6.28(s, 2H), 6.32(s, 1H), 7.87(bs, 1H), 8.05(bs, 1H). 48% yield, 11.1 gfrom 26.8 g. 270 (2-OEt)Ph mp 180-181° C.: ¹H NMR(DMSO-d₆)δ1.30(t, 3H),2.90(dd, 1H), 2.99(dd, 1H), 3.12(d, 1H), 3.35(d, 1H), 3.91(m, 1H),3.93(q, 2H), 6.79(t, 1H), 6.88(d, 1H), 7.05(d, 1H), 7.18(t, 1H),7.79(bs, 1H), 7.86(bs, 1H). 65% yield, 16.5 g gave 9.2 g. 271(2-O-i-Pr)Ph mp 217-218° C.; ¹H NMR(DMSO-d₆)δ1.24(d, 6H), 2.6-3.4(m,4H), 3.89(m, 1H), 4.52(m, 1H), 6.78(t, 1H), 6.88(d, 1H), 7.06(d, 1H),7.16(d, 1H), 7.77(s, 1H), 7.88(s, 1H). 272 (4-i-Pr)Ph mp > 250° C.: ¹HNMR(DMSO-d₆)δ1.14(d, 6H), 2.71(d, 1H), 2.81(septet, 1H), 2.82(dd, 1H),3.01(dd, 1H), 3.30(d, 1H), 4.00(m, 1H), 7.04(d, 2H), 7.10(d, 2H),7.83(bs, 1H), 8.09(bs, 1H). 78% yield, 32.6 g gave 22.4 g. 273(3,5-Di-CH₃)Ph mp 210-211° C.: ¹H NMR(DMSO-d₆)δ2.16(s, 6H), 2.77(dd,1H), 2.79(d, 1H), 2.94(dd, 1H), 3.32(d, 1H), 3.98(m, 1H), 6.73(s, 2H),6.84(s, 1H), 7.86(bs, 1H), 8.07(bs, 1H). 90% yield, 15.8 g gave 12.2 g.274 (4-OPh)Ph mp 226-228° C.: ¹H NMR(DMSO-d₆) δ2.85(dd, 1H), 2.91(d,1H), 3.02(dd, 1H), 3.40(d, 1H), 4.02(m, 1H), (6.93(d, 2H), 6.94(d, 1H),7.09(t, 1H), 7.14(d, 1H), 7.35(t, 2H), 7.89(bs, 1H), 8.12(bs, 1H). 98%yield, 37.0 g gave 32.1 g. 275 (Pyrid-2-yl) ¹H NMR(DMSO-d₆)δ3.14(m, 2H),3.41(d, 1H), 3.54(d, 2H), 4.17(m, 1H), 7.19-7.23(m, 2H), 7.68(t, 1H),7.93(bs, 1H), 8.01(bs, 1H), 8.45(d, 1H). 276 (2,4-Di-OCH₃)Ph mp 221-223°C.: ¹H NMR(DMSO-d₆) δ2.77(dd, 1H), 2.90(dd, 1H), 3.14(d, 1H), 3.33(d,1H), 3.79(m, 1H), 6.38(d, 1H), 6.45(s, 1H), 6.91(d, 1H), 7.75(bs, 1H),7.83(bs, 1H).

Example 280 (S)-1,4-Dibenzyl-2-[2-(4-chloro-phenyl)-ethyl]-pipierazine

Combine (S)-1,4-dibenzyl-2-vinyl-piperazine (5.0 g, 17.10 mmol) and9-borabicyclo[3.3.1]nonane (136.8 ml, 68.39 mmol, 0.5 M in THF) and stirat ambient temperature. After 24 hrs, add 1-iodo-4-chloro-benzene (6.12g, 25.65 mmol), triphenylphosphine (717.5 mg, 2.74 mmol),tetrakis(triphenylphosphine) palladium(0)(395.1 mg, 0.34 mmol), and 3NNaOH (14.0 ml) and stir at 60°. After 22 hrs, remove the THF undervacuum, stir the residue in 2N NaOH, and extract with diethyl ether.Wash the organic with 1N H₂SO₄ then adjust the aqueous to pH 14. Extractthe aqueous with diethyl ether and combine, wash (brine), dry (sodiumsulfate), and reduce the extracts to residue. Recrystallize the residuein warm ethanol to give 4.76 g (69%) of the title compound: mp 87°-90°;mass spectrum (ion spray): m/z=405.4 (M+1); Analysis for C₂₆H₂₉ClN₂:calcd: C, 77.11; H, 7.22; N, 6.92; found: C, 76.93; H, 7.06; N, 7.01.

Example 281 (S)-1,4-Dibenzyl-2-[2-(3-chloro-phenyl)-ethyl]-piperazine

Combine (S)-1,4-dibenzyl-2-vinyl-piperazine (5.0 g, 17.10 mmol) and9-borabicyclo[3.3.1]nonane (136.8 ml, 68.39 mmol, 0.5 M in THF) and stirat ambient temperature. After 24 hrs, add 1-iodo-3-chloro-benzene (6.12g, 25.65 mmol), triphenylphosphine (717.5 mg, 2.74 mmol),tetrakis(triphenylphosphine)palladium(0)(395.1 mg, 0.34 mmol), and 3NNaOH (14.0 ml) and stir at 60°. After 22 hrs, remove the THF undervacuum, stir the residue in 2N NaOH, and extract with diethyl ether.Wash the organic with 1N H₂SO₄ then adjust the aqueous to pH 14. Extractthe aqueous with diethyl ether and combine, wash (brine), dry (sodiumsulfate), and reduce the extracts to residue. Recrystallize the residuein warm ethanol to give 5.01 g (72%) of the title compound: mp 56°-60°;mass spectrum (ion spray): m/z=405.4 (M+1).

Example 282 (S)-1,4-Dibenzyl-2-[2-(2-chloro-phenyl)-ethyl]-pipierazine

Combine (S)-1,4-dibenzyl-2-vinyl-piperazine (6.0 g, 20.52 mmol) and9-borabicyclo[3.3.1]nonane (164.1 ml, 82.07 mmol, 0.5 M in THF) and stirat ambient temperature. After 24 hrs, add 1-iodo-2-chloro-benzene (7.34g, 30.78 mmol), triphenylphosphine (861.0 mg, 3.28 mmol),tetrakis(triphenylphosphine)palladium(0)(474.1 mg, 0.41 mmol), and 3NNaOH (16.8 ml) and stir at 60°. After 22 hrs, remove the TIIF undervacuum, stir the residue in 2N NaOH, and extract with diethyl ether.Wash the organic with 1N H₂SO₄ then adjust the aqueous to pH 14. Extractthe aqueous with diethyl ether and combine, wash (brine), dry (sodiumsulfate), and reduce the extracts to residue. Recrystallize the residuein warm ethanol to give 2.59 g (31%) of the title compound: massspectrum (ion spray): m/z=405.4 (M+1); Analysis for C₂₆H₂₉ClN₂: calcd:C, 77.11; H, 7.22; N, 6.92; found: C, 77.12; H, 7.13; N, 7.07.

Example 283(S)-1,4-Dibenzyl-2-[2-(4-trifluoromethyl-phenyl)-ethyl]-piperazine

Combine (S)-1,4-dibenzyl-2-vinyl-piperazine (6.0 g, 20.52 mmol) and9-borabicyclo[3.3.1]nonane (164.1 ml, 82.07 mmol, 0.5 M in THF) and stirat ambient temperature. After 24 hrs, add1-iodo-4-trifluoromethyl-benzene (8.37 g, 30.78 mmol),triphenylphosphine (861.0 mg, 3.28 mmol),tetrakis(triphenylphosphine)palladium(0 )(474.1 mg, 0.41 mmol), and 3NNaOH (16.8 ml) and stir at 60°. After 22 hrs, remove the THF undervacuum, stir the residue in 2N NaOH, and extract with diethyl ether.Wash the organic with 1N H₂SO₄ then adjust the aqueous to pH 14. Extractthe aqueous with diethyl ether and combine, wash (brine), dry (sodiumsulfate), and reduce the extracts to residue. Recrystallize the residuein warm ethanol to give 3.34 g (37%) of the title compound: massspectrum (ion spray): mp 71°-75°; m/z=439.2 (M+1); Analysis forC₂₇H₂₉F₃N₂: calcd: C, 73.95; H, 6.67; N, 6.39; found: C, 74.15; H, 6.72;N, 6.52.

Example 284(S)-1,4-Dibenzyl-2-[2-(2-trifluoromethyl-phenyl)-ethyl]-piperazine

Combine (S)-1,4-dibenzyl-2-vinyl-piperazine (6.0 g, 20.52 mmol) and9-borabicyclo[3.3.1]nonane (164.1 ml, 82.07 mmol, 0.5 M in THF) and stirat ambient temperature. After 24 hrs, add1-iodo-2-trifluoromethyl-benzene (8.37 g, 30.78 mmol),triphenylphosphine (861.0 mg, 3.28 mmol),tetrakis(triphenylphosphine)palladium(0)(474.1 mg, 0.41 mmol), and 3NNaOH (16.8 ml) and stir at 60°. After 22 hrs, remove the THF undervacuum and dissolve the residue in ethyl acetate. Wash the organic layerwith 1N NaOH then combine, wash (brine), dry (sodium sulfate), andreduce the extracts to residue. Purify the residue using ethylacetate/hexanes (5:95) and reduce the appropriate fractions to residue.Stir the residue in 2N NaOH, and extract with diethyl ether. Wash theorganic with 1N H₂SO₄ then adjust the aqueous to pH 14. Extract theaqueous with diethyl ether and combine, wash (brine), dry (sodiumsulfate), and reduce the extracts to residue. Recrystallize the residuein warm ethanol to give 2.67 g (30%) of the title compound: massspectrum (ion spray): mp 77°-82°; m/z=439.2 (M+1); Analysis forC₂₇H₂₉F₃N₂: calcd: C, 73.95; H, 6.67; N, 6.39; found: C, 74.11; H, 6.68;N, 6.50.

Example 285 (S)-2-[2-(4-Trifluoromethyl-phenyl)-ethyl]-piperazine

Combine(S)-1,4-dibenzyl-2-[2-(4-trifluoromethyl-phenyl)-ethyl]-piperazine (3.34g, 7.62 mmol), ammonium formate (2.40 g, 38.09 mmol), 5% Pd/C (368.7mg), and ethanol (100 ml). Stir and heat the mixture at reflux. After 3hrs, cool to ambient temperature and remove the catalyst by vacuumfiltration through celite. Reduce the filtrate to residue and thendissolve it in dichloromethane. Wash the organic with 1N NaOH and thencombine, wash (brine), dry (sodium sulfate), and reduce the extracts toresidue to give 1.83 g (93%) of the title compound as an off-whitesolid: mp 135°-141°; mass spectrum (ion spray): m/z=259.2 (M+1).

Example 286 (S)-2-[2-(2-Trifluoromethyl-phenyl)-ethyl]-piperazine

Combine(S)-1,4-dibenzyl-2-[2-(2-trifluoromethyl-phenyl)-ethyl]-piperazine (2.66g, 6.06 mmol), ammonium formate (1.91 g, 30.31 mmol), 5% Pd/C (293.3mg), and ethanol (100 ml). Stir and heat the mixture at reflux. After 3hrs, cool to ambient temperature and remove the catalyst by vacuumfiltration through celite. Reduce the filtrate to residue. Purify theresidue on silica gel using dichloromethane/2N ammonia in methanol(90:10) to give 1.46 g (93%) of the title compound as a white solid: mp43°-47°; mass spectrum (ion spray): m/z=259.2 (M+1).

Example 287 (S)-2-[2-(2-chloro-phenyl)-ethyl]-piperazine

Dissolve (S)-1,4-dibenzyl-2-[2-(2-chloro-phenyl)-ethyl]-piperazine (2.59g, 6.38 mmol) in dichloroethane (30 ml). Cool the solution to 0° andthen add 1-chloroethyl chloroformate (2.74 g, 19.15 mmol) dropwise. Warmthe solution to ambient temperature and then heat it at reflux for 15hours. Remove the dichloroethane under vacuum and reflux the resultingresidue in methanol for 1 hour. Remove the methanol under vacuum anddissolve the resulting precipitate in 1N NaOH. Extract the aqueous layerwith dichloromethane and then combine, wash (brine), dry (sodiumsulfate), and reduce the extracts to residue. Purify the residue onsilica gel using dichloromethane/2N ammonia in methanol (90:10) to give482.4 mg (34%) of the title compound: mass spectrum (ion spray):m/z=225.3 (M+1).

Example 288 (S)-2-[2-(4-chloro-phenyl)-ethyl]-piperazine

Dissolve (S)-1,4-dibenzyl-2-[2-(4-chloro-phenyl)-ethyl]-piperazine (4.74g, 11.71 mmol) in dichloroethane (80 ml). Cool the solution to 0° andthen add 1-chloroethyl chloroformate (7.95 g, 55.61 mmol) dropwise. Warmthe solution to ambient temperature and then heat it at reflux for 15hours. Remove the dichloroethane under vacuum and reflux the resultingresidue in methanol for 1 hour. Remove the methanol under vacuum anddissolve the resulting precipitate in 1N NaOH. Extract the aqueous layerwith dichloromethane and then combine, wash (brine), dry (sodiumsulfate), and reduce the extracts to residue. Purify the residue onsilica gel using dichloromethane/2N ammonia in methanol (90: 10) to give459.0 mg (18%) of the title compound: mp 140°-144°; mass spectrum (ionspray): m/z=225.3 (M+1).

Example 289 (S)-2-[2-(3-chloro-phenyl)-ethyl]-piperazine

Dissolve (S)-1,4-dibenzyl-2-[2-(3-chloro-phenyl)-ethyl]-piperazine (4.48g, 11.07 mmol) in dichloroethane (40 ml). Cool the solution to 0° andthen add 1-chloroethyl chloroformate (4.75 g, 33.21 mmol) dropwise. Warmthe solution to ambient temperature and then heat it at reflux for 42hours. Remove the dichloroethane under vacuum and reflux the resultingresidue in methanol (100 ml) for 1 hour. Remove the methanol undervacuum and dissolve the resulting precipitate in 1N NaOH. Extract theaqueous layer with dichloromethane and then combine, wash (brine), dry(sodium sulfate), and reduce the extracts to residue. Purify the residueon silica gel using dichloromethane/2N ammonia in methanol (90:10) togive 407.6 mg (16%) of the title compound: mp 93°-97°; mass spectrum(ion spray): m/z=225.3 (M+1).

Example 290 1,4-Dibenzyl-2-[2-(2,5-difluoro-phenyl)-ethyl]-piperazine

Prepared in a similar fashion to Example 284,Yield 23%, mass spectrum(m/e): 407.3 (M+1)

Example 291 2-[2-(2,5-Difluoro-phenyl)-ethyl]-piperazine

Dissolve1,4-dibenzyl-2-[2-(2,5-difluoro-phenyl)-ethyl]-piperazine (2.7g, 6.6 mmol) in methanol (25 ml) and add 10% palladium on carbon (wet,1.0 g). Carry out the hydrogenation with a hydrogen balloon at roomtemperature for 16 hours. Filter the reaction mixture, concentrate thefiltrate under reduced pressure to give2-[2-(2,5-difluoro-phenyl)-ethyl]-piperazine as an oil (1.5 g, 100%).mass spectrum (mnle): 227.0 (M+1).

Example 2921,4-Dibenzyl-2-[2-(3-trifluoromethyl-phenyl)-ethyl]-piperazine

Prepared in a similar fashion to Example 284: Yield 73%, mass spectrum(m/e): 439.3 (M+1)

Example 293 2-[2-(3-Trifluoromethyl-phenyl)-ethyl]-piperazine

Prepared in a similar fashion to Example 286. Yield 100%, mass spectrum(m/e): 259.1 (M+1).

Example 3732-Methyl-4,9-dihydro-3-thia-6-fluoro-4,9-diazabenzo[f]azulene-10-thione

Suspend2-methyl-4,9-dihydro-3-thia-6-fluoro-4,9-diazabenzo[f]azulene-10-one(1.2 g, 4.8 mmol) in dry toluene and add Lawesson's reagent ( 1.1 g, 2.7mmol) under nitrogen. Heat the reaction mixture under reflux for onehour and cool overnight. Precipate the desired material and collect byfiltration, air-dry for several minutes to give 529 mg of yellow solidwhich can be used in the next step without further purification. MassSpectrum (FIA) 265 (M+1); ¹H NMR (300 MHz, CDCl₃): 6.98 (s, 1H), 6.75(t, 1H), 6.6 (t, 1H), 6.43 (d, 1H), 3.29 (s, 1H), 2.21 (s, 3H)

Example 374 2-Amino-5-tert-butyl-thiophene-3-carbonitrile

Add a solution of 3,3-dimethyl-butyraldehyde (20 g, 200 mmol) in EtOH(40 mL) dropwise a mixture of sulfur (6.4 g, 200 mmol), malononitrile(13.2 g, 200 mmol) and triethylamine (14.3 mL, 100 mmol) in EtOH (400mL) at 0° C. Stir the mixture at room temperature for 20 minutes afterthe addition is complete, then reflux for 2 hours. Cool, concentrate toa paste. Add diethyl ether (200 mL) and 2N HCl (200 mL). Wash theorganic layer again with 2N HCl, dry (Na₂SO₄), and concentrate. Purifythe residue via column chromatography eluting with methylene chloride toafford the title compound as tan crystals (16.9 g, 47%): ¹H NMR (CDCl₃)δ 1.27 (s, 9H), 4.60 (bs, 2H), 6.36 (s, 1H).

Example 375 2-Amino-5-iso-propyl-thiophene-3-carbonitrile

Substitute isovaleraldehyde for 3,3-dimethyl-butyraldehyde and use themethod of Example 374 to obtain the title compound as a brown solid: ¹HNMR (CDCl₃) δ1.24 (d, 6H), 2.93 (septet, 1H), 6.37 (s, 1H).

Example 376 2-Amino-5-cyclopentyl-thiophene-3-carbonitrile

Substitute 2-cyclopentylacetaldehyde for 3,3-dimethyl-butyraldehyde andsubstitute DMF for EtOH and use the method of Example 374 to obtain thetitle compound (16.1 g, 57%) as a yellow solid: ¹H NMR (CDCl₃) δ1.48-1.58 (m, 2H), 1.61-1.69 (m, 2H), 1.72-1.78 (m, 2H), 1.98-2.07 (m,2H), 3.01 (m, 1H), 4.58 (bs, 2H), 6.38 (s, 1H).

Example 3785-tert-Butyl-2-(2-nitro-phenylamino)-thiophene-3-carbonitrile

Add a solution of 2-amino-5-tert-butyl-thiophene-3-carbonitrile (16.9 g,94 mmol) in THF (50 mL) to a mixture of washed NaH (from 6.76 g of 60%mineral oil dispersion) in THF (200 mL) in a water bath at roomtemperature. Stir 15 minutes, then add a solution of2-fluoro-nitrobenzene (13.2 g, 94 mmol) in THF (50 mL) dropwise. Stirovernight. Pour the purple reaction mixture unto 6 N HCl (400 mL).Extract the mixture with diethyl ether (400 mL). Wash the etherlayerwith 2 N HCl (400 mL), brine (250 mL), dry (Na₂SO₄), andconcentrate to afford a mixture of crystals in a dark oily residue.Triturate the crystals with hexanes and filter to afford the titlecompound as a red powder (21.2 g, 75%) mp 85-90° C.: ¹H NMR (CDCl₃) δ1.39 (s, 9H), 6.81 (s, 1H), 6.97 (t, 1H), 7.23 (d, 1H), 7.53 (t, 1H),8.25 (d, 1H), 9.66 (bs, 1H).

By the method of example 378, the following compounds were prepared andisolated as the free base:

No: R¹ Data 379 i-Pr ¹H NMR(CDCl₃)δ1.35(d, 6H), 3.13(septet, 1H),6.80(s, 1H), 6.96(t, 1H), 7.22(d, 1H), 7.54(t, 1H), 8.24(d, 1H), 9.65(s,1H). 380 c-Pentyl ¹H NMR(CDCl₃)δ1.56-1.84(m, 6H), 2.11-2.19(m, 2H),3.18(pentet, 1H), 6.80(s, 1H), 6.96(t, 1H), 7.21(d, 1H), 7.53(t, 1H),8.25(d, 1H), 9.64(s, 1H).

Example 381 2-tert-Butyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylaminehydrochloride

Add 5-tert-butyl-2-(2-nitro-phenylamino)-thiophene-3-carbonitrile (21.2g, 70 mmol) to a solution of tin(II)chloride dihydrate (46.1 g, 209mmol) in conc. HCl (200 mL) and ethanol (600 mL). Reflux the mixture for2 hours. Concentrate the solution to 200 mL and add to water (1 L).Filter and wash with water then hexanes to obtain the title compound asan orange powder (19.4 g): ¹H NMR (DMSO-d₆) δ 1.27 (s, 9H), 6.86 (d,1H), 6.89 (s, 1H), 6.95 (d, 1H), 7.03 (t, 1H), 7.11 (t, 1H), 8.69 (s,1H) 9.11 (s, 1), 9.52 (s, 1H), 10.88 (s, 1H); MS (APCI) m/z (relintensity) 272 (100).

By the method of example 381, the following compounds were prepared andisolated as the free base:

No. R Data 382 i-Pr ¹H NMR(DMSO-d₆)δ1.16(d, 6H), 2.88(septet, 1H),6.82(s, 1H), 6.83(d, 1H), 6.91(d, 1H), 6.99(t, 1H), 7.07(t, 1H), 8.71(s,1H), 9.09(s, 1H), 9.54(s, 1H), 10.94(s, 1H). 383 c-Pentyl ¹HNMR(DMSO-d₆)δ1.42-1.70(m, 6H), 1.92-2.00(m, 2H), 2.99(pentet, 1H),6.81(s, 1H), 6.82(d, 1H), 6.91(d, 1H), 6.99(t, 1H), 7.07(t, 1H),8.63(bs, 1H), 9.05(bs, 1H), 9.50(bs, 1H), 10.79(bs, 1H).

Example 3842-tert-Butyl-10-(4-methyl-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene

By a method similar to Example 59, using2-tert-butyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine hydrochloride(1.00 g, 3.26 mmol) and N-methyl-piperazine (1.9 g, 19 mmol) to obtainthe title compound (904 mg, 78%) as a yellow powder: mp 125-130° C.(dec): ¹H NMR (CDCl₃) δ 1.29 (s, 9H), 2.35 (s, 3H), 2.50 (m, 4H), 3.53(m, 4H), 4.96 (s, 1H), 6.33 (s, 1H), 6.60 (d, 1H), 6.87 (t, 1H), 6.96(t, 1H), 7.02 (d, 1).

By a method similar to Example 59, the following compounds were preparedand isolated as the free base:

No: R² Data 385 i-Pr ¹H NMR(CDCl₃)δ1.23(d, 6H), 2.34(s, 3H), 2.50(m,4H), 2.95(septet, 1H), 3.53(m, 4H), 5.00(s, 1H), 6.32(s, 1H), 6.60(d,1H), 6.87(t, 1H), 6.97(t, 1H), 7.02(d, 1H); MS(APCI)m/z(relintensity)581(100), 341(80). 386 c-Pentyl ¹H NMR(CDCl₃)δ1.48-1.79(m,6H), 2.02(m, 2H), 2.35(s, 3H), 2.50(m, 4H), 3.04(pentet, 1H), 3.53(m,4H), 4.95(s, 1H), 6.33(s, 1H), 6.60(d, 1H), 6.87(t, 1H), 6.97(t, 1H),7.03(d, 1H); MS(APCI)m/z(rel intensity)367 (100).

Example 38710-((S)-3-[2-(3-Chloro-phenyl)-ethyl]-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylaminehydrochloride (829.8 mg, 3.12 mmol),(S)-2-[2-(3-chloro-phenyl)-ethyl]-piperazine (1.40 g, 6.24 mmol),N,N-diisopropylethylamine (403.6 mg, 3.12 mmol), DMSO (1.0 ml), andtoluene (4.0 ml). Stir and heat the mixture at 105° C. After 48 hours,cool the mixture to ambient temperature and then dilute it with ethylacetate and water. Remove the organic layer and wash it with 1N NaOH andbrine. Dry (sodium sulfate) and concentrate the organic layer toresidue. Purify the residue on silica gel using dichloromethane/methanol(95:5) to give 673.9 mg (50%) of the title compound as a brown foam: mp68-74°, dec; mass spectrum (ES+): m/e=437.31.

Example 38810-((S)-3-[2-(4-Chloro-phenyl)-ethyl]-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylaminehydrochloride (642.0 mg, 2.42 mmol),(S)-2-[2-(4-chloro-phenyl)-ethyl]-piperazine (1.09 g, 4.83 mmol),N,N-diisopropylethylamine (312.2 mg, 2.42 mmol), DMSO (1.0 ml), andtoluene (4.0 ml). Stir and heat the mixture at 105° C. After 48 hours,cool the mixture to ambient temperature and then dilute it with ethylacetate and water. Remove the organic layer and wash it with 1N NaOH andbrine. Dry (sodium sulfate) and concentrate the organic layer toresidue. Purify the residue on silica gel using dichloromethane/methanol(95:5) to give 501.6 mg (47%) of the title compound as a brown foam: mp91°, dec; mass spectrum (ion spray): m/z=437.3.

Example 389 10-((S)-3-[2-(2-Chloro-phenyl)-ethyl]-piperazin-l-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylaminehydrochloride (607.1 mg, 2.28 mmol),(S)-2-[2-(2-chloro-phenyl)-ethyl]-piperazine (1.03 g, 4.57 mmol),N,N-diisopropylethylamine (295.3 mg, 2.28 mmol), DMSO (1.0 ml), andtoluene (4.0 ml). Stir and heat the mixture at 105° C. After 64 hours,cool the mixture to ambient temperature and then dilute it with ethylacetate and water. Remove the organic layer and wash it with 1N NaOH andbrine. Dry (sodium sulfate) and concentrate the organic layer toresidue. Purify the residue on silica gel using dichloromethane/methanol(95:5) to give 482.4 mg (48%) of the title compound as a brown foam: mp72°, dec; mass spectrum (ion spray): m/z=437.3.

Example 39010-((S)-3-[2-(4-Chloro-phenyl)-ethyl]-4-methyl-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine10-((S)-3-[2-(4-chloro-phenyl)-ethyl]-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene(430.9 mg, 0.99 mmol), formaldehyde (88.0 μL, 1.08 mmol, 37% in water),and 1,2-dichloroethane (30.0 ml). Stir the mixture at ambienttemperature for 5 minutes and then add sodium triacetoxyborohydride(313.5 mg, 1.48 mmol). After stirring for 30 minutes at ambienttemperature, quench the reaction with saturated sodium bicarbonate.Remove the organic portion, extract the aqueous with dichloromethane andcombine, wash (brine), dry (sodium sulfate), and reduce the extracts toresidue. Purify the residue on silica gel using dichloromethane/methanol(95:5) to give 365.2 mg (82%) of the title compound as a brown foam: mp79°, dec; mass spectrum (ion spray): m/z=451.2 (M+1).

Example 39110-((S)-3-[2-(3-Chloro-phenyl)-ethyl]-4-methyl-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine10-((S)-3-[2-(3-chloro-phenyl)-ethyl]-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene(608.3 mg, 1.53 mmol), formaldehyde (124.3 μL, 1.53 mmol, 37% in water),and 1,2-dichloroethane (30.0 ml). Stir the mixture at ambienttemperature for 5 minutes and then add sodium triacetoxyborohydride(442.5 mg, 2.09 mmol). After stirring for 30 minutes at ambienttemperature, quench the reaction with saturated sodium bicarbonate.Remove the organic portion, extract the aqueous with dichloromethane andcombine, wash (brine), dry (sodium sulfate), and reduce the extracts toresidue. Purify the residue on silica gel using dichloromethane/methanol(95:5) to give 502.3 mg (80%) of the title compound as a brown foam: mp69°, dec; mass spectrum (ion spray): m/z=451.2 (M+1).

Example 39210-((S)-3-[2-(2-Chloro-phenyl)-ethyl]-4-methyl-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine10-((S)-3-[2-(2-chloro-phenyl)-ethyl]-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene(398.3 mg, 0.91 mmol), formaldehyde (81.4 μL, 1.00 mmol, 37% in water),and 1,2-dichloroethane (30.0 ml). Stir the mixture at ambienttemperature for 5 minutes and then add sodium triacetoxyborohydride(289.7 mg, 1.37 mmol). After stirring for 30 minutes at ambienttemperature, quench the reaction with saturated sodium bicarbonate.Remove the organic portion, extract the aqueous with dichloromethane andcombine, wash (brine), dry (sodium sulfate), and reduce the extracts toresidue. Purify the residue on silica gel using dichloromethane/methanol(95:5) to give 341.6 mg (83%) of the title compound as a brown foam: mp72°, dec; mass spectrum (ion spray): m/z=451.1 (M+1).

Example 39310-((S)-3-[2-(4-Trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylaminehydrochloride (514.5 mg, 1.94 mmol),(S)-2-[2-(4-trifluoromethyl-phenyl)-ethyl]-piperazine (1.00 g, 3.87mmol), N,N-diisopropylethylamine (250.2 mg, 1.94 mmol), DMSO (1.0 ml),and toluene (4.0 ml). Stir and heat the mixture at 105° C. After 48hours, cool the mixture to ambient temperature and then dilute it withethyl acetate and water. Remove the organic layer and wash it with 1NNaOH and brine. Dry (sodium sulfate) and concentrate the organic layerto residue. Purify the residue on silica gel usingdichloromethane/methanol (95:5) to give 380.3 mg (42%) of the titlecompound as a brown foam: mp 78°, dec; mass spectrum (ion spray):m/z=471.1.

Example 39410-((S)-3-[2-(2-Trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylaminehydrochloride (514.5 mg, 1.94 mmol),(S)-2-[2-(2-trifluoromethyl-phenyl)-ethyl]-piperazine (1.00 g, 3.87mmol), N,N-diisopropylethylamine (250.2 mg, 1.94 mmol), DMSO (1.0 ml),and toluene (4.0 ml). Stir and heat the mixture at 105° C. After 48hours, cool the mixture to ambient temperature and then dilute it withethyl acetate and water. Remove the organic layer and wash it with 1NNaOH and brine. Dry (sodium sulfate) and concentrate the organic layerto residue. Purify the residue on silica gel usingdichloromethane/methanol (95:5) to give 497.4 mg (55%) of the titlecompound as a brown foam: mp 73°, dec; mass spectrum (ion spray):m/z=471.1.

Example 39510-((S)-3-[2-(3-Trifluoromethyl-phenyl)-ethyl]-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylaminehydrochloride (514.5 mg, 1.94 mmol),(S)-2-[2-(3-trifluoromethyl-phenyl)-ethyl]-piperazine (1.00 g, 3.87mmol), N,N-diisopropylethylamine (250.2 mg, 1.94 mmol), DMSO (1.0 ml),and toluene (4.0 ml). Stir and heat the mixture at 105° C. After 64hours, cool the mixture to ambient temperature and then dilute it withethyl acetate and water. Remove the organic layer and wash it with 1NNaOH and brine. Dry (sodium sulfate) and concentrate the organic layerto residue. Purify the residue on silica gel usingdichloromethane/methanol (95:5) to give 370.6 mg (41%) of the titlecompound as a brown foam: mp 69°, dec; mass spectrum (ion spray):m/z=471.1.

Example 39610-((S)-3-[2-(4-Trifluoromethyl-phenyl)-ethyl]-4-methyl-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine10-((S)-3-[2-(4-trifluromethyl-phenyl)-ethyl]-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene(325.3 mg, 0.69 mmol), formaldehyde (61.7 μL, 0.76 mmol, 37% in water),and 1,2-dichloroethane (30.0 ml). Stir the mixture at ambienttemperature for 5 minutes and then add sodium triacetoxyborohydride(219.8 mg, 1.04 mmol). After stirring for 30 minutes at ambienttemperature, quench the reaction with saturated sodium bicarbonate.Remove the organic portion, extract the aqueous with dichloromethane andcombine, wash (brine), dry (sodium sulfate), and reduce the extracts toresidue. Purify the residue on silica gel using dichloromethane/methanol(95:5) to give 298.1 mg (89%) of the title compound as a tan foam: mp72°, dec; mass spectrum (ion spray): m/z=485.2 (M+1).

Example 39710-((S)-3-[2-(2-Trifluoromethyl-phenyl)-ethyl]-4-methyl-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine10-((S)-3-[2-(2-trifluromethyl-phenyl)-ethyl]-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene(365.7 mg, 0.78 mmol), formaldehyde (69.4 μL, 0.85 mmol, 37% in water),and 1,2-dichloroethane (30.0 ml). Stir the mixture at ambienttemperature for 5 minutes and then add sodium triacetoxyborohydride(247.0 mg, 1.17 mmol). After stirring for 30 minutes at ambienttemperature, quench the reaction with saturated sodium bicarbonate.Remove the organic portion, extract the aqueous with dichloromethane andcombine, wash (brine), dry (sodium sulfate), and reduce the extracts toresidue. Purify the residue on silica gel using dichloromethane/methanol(95:5) to give 304.3 mg (81%) of the title compound as a tan foam: mp68°, dec; mass spectrum (ion spray): m/z=485.2 (M+1).

Example 39810-C(S)-3-[2-(3-Trifluorometyl-phenyl)-ethyl]-4-methyl-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine10-((S)-3-[2-(3-trifluromethyl-phenyl)-ethyl]-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene(287.3 mg, 0.61 mmol), formaldehyde (54.5 μL, 0.67 mmol, 37% in water),and 1,2-dichloroethane (30.0 ml). Stir the mixture at ambienttemperature for 5 minutes and then add sodium triacetoxyborohydride(194.1 mg, 0.92 mmol). After stirring for 30 minutes at ambienttemperature, quench the reaction with saturated sodium bicarbonate.Remove the organic portion, extract the aqueous with dichloromethane andcombine, wash (brine), dry (sodium sulfate), and reduce the extracts toresidue. Purify the residue on silica gel using dichloromethane/methanol(95:5) to give 228.0 mg (77%) of the title compound as a tan foam: mp62°, dec; mass spectrum (ion spray): m/z=485.3 (N+1).

Example 39910-((S)-3-[2-(2,4-Difluoro-phenyl)-ethyl]-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine 2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylaminehydrochloride (351.6 mg, 1.32 mmol),(S)-2-[2-(2,4-difluoro-phenyl)-ethyl]-piperazine (600.0 mg, 2.65 mmol),N,N-diisopropylethylamine (171.0 mg, 1.32 mmol), DMSO (0.6 ml), andtoluene (2.4 ml). Stir and heat the mixture at 105° C. After 48 hours,cool the mixture to ambient temperature and then dilute it with ethylacetate and water. Remove the organic layer and wash it with 1N NaOH andbrine. Dry (sodium sulfate) and concentrate the organic layer toresidue. Purify the residue on silica gel using dichloromethane/methanol(95:5) to give 91.8 mg (16%) of the title compound as a brown foam: mp69°, dec; mass spectrum (ion spray): m/z=439.0.

Example 40010-((S)-3-[2-(2,4-Difluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine10-((S)-3-[2-(2,4-difluoro-phenyl)-ethyl]-piperazin-1-yl)-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene(57.3 mg, 0.61 mmol), formaldehyde (11.7 μL, 0.14 mmol, 37% in water),and 1,2-dichloroethane (5.0 ml). Stir the mixture at ambient temperaturefor 5 minutes and then add sodium triacetoxyborohydride (41.5 mg, 0.20mmol). After stirring for 30 minutes at ambient temperature, quench thereaction with saturated sodium bicarbonate. Remove the organic portion,extract the aqueous with dichloromethane and combine, wash (brine), dry(sodium sulfate), and reduce the extracts to residue to give 54.4 mg(92%) of the title compound: mass spectrum (ion spray): m/z=452.9 (M+1).

Example 4016-Fluoro-10-{3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Suspend2-methyl-4,9-dihydro-3-thia-6-fluoro-4,9-diazabenzo[f]azulene-10-thione(370 mg, 1.4 mmol) in dichloromethane (30 ml), stir under nitrogen andcool in an ice/water bath. Addmethyl trifluoromethanesulfonate (400 μl),and stir the reaction mixture overnight. Concentrate the reactionmixture under reduced pressure, take up in pyridine (10 ml) and add(S-2[2′-(3-fluorophenyl)-ethyl]-piperazine) (300 mg, 1.4 mmol). Stir thereaction mixture under nitrogen and heat at 90° C. overnight.Concentrate the reaction mixture under reduced pressure and purify byflash column chromatography on silica gel (eluentdichloromethane/methanol) to give the desired as a light green oil 575mg: mass Spectrum (FIA) 439 (M+1); NMR (¹H, 300 MHz, CDCl₃): 7.2 (m,1H),7.0 (m,1H), 6.93 (m,1H), 6.85 (m,2H), 6.68 (m,1H), 6.49 (m,1H), 6.22(s,1H), 5.95 broad, 1H), 4.12 (m,1H), 4.0(m,1H), 3.28 (m,2H), 3.05(m,3H), 2.69 (m,2H), 2.29 (s, 3H), 1.88 (m,2H).

Example: 4026-Fluoro-10-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Similarly prepared using Example 401, using2-methyl-4,9-dihydro-3-thia-6-fluoro-4,9-diazabenzo[f]azulene-10-thioneand (5-2[2′-(4-methoxyphenyl)-ethyl]-piperazine): mass Spectrum (FIA)451 (M+1); NMR (¹H, 300 MHz, CDCl₃): 7.10 (d,2H), 6.94 (m,1H), 6.82(d,2H), 6.68 (m,1H), 6.38 (m,1H), 6.28 (s,1H), 5.07 broad, 1H), 4.02(m,1H), 3.87(m,1H), 3.78 (s,3H), 3.12 (m,1H), 2.8-2.9 (m,2H), 2.7(m,1H), 2.55 (m,1H), 2.29 (s, 3H), 1.9 (m,2H), 1.7 (m,2H).

Example 4037-Fluoro-10-{3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Similarly prepared using Example 401, using2-methyl-4,9-dihydro-3-thia-7-fluoro-4,9-diazabenzo[f]azulene-10-thioneand (S-2[2′-(3-fluorophenyl)-ethyl]-piperazine): mass Spectrum (FIA) 439(M+1); NMR (¹H, 300 MHz, CDCl₃): 7.22 (m,1H), 6.95 (m,1H), 6.88 (m, 2H),6.72 (m,1H), 6.5-6.7 (m,2H), 6.24 (s,1H), 5.05 (broad,1H), 4.22 (m, 1H),4.03 (m,1H), 3.30 (m,2H), 3.10 (m,3H), 2.69 (m,2H), 2.32 (s, 3H), 1.93(m,2H).

Example 4047-Fluoro-10-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Similarly prepared using Example 401, using2-methyl-4,9-dihydro-3-thia-7-fluoro-4,9-diazabenzo[f]azulene-10-thioneand (S-2[2′-(4-methoxyphenyl)-ethyl]-piperazine): mass Spectrum (FIA)451 (M+1); NMR (¹H, 300 MHz, CDCl₃): 7.05 (d,2H), 6.79 (d,2H), 6.70(m,1H), 6.52-6.68 (m,2H), 6.22 (s,1H), 5.13 (broad,1H), 4.22 (m,1H),4.02 (m,1H), 3.74 (s,3H), 3.3-3.4 (m,2H), 3.03-3.27 (m,3H), 2.63 (m,2H),2.33 (s,3H), 1.9-2.1 (m,2H).

Example 4056-Fluoro-10-{3-[2-(3-fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulenehydrochloride

Dissolve6-fluoro-10-{3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene(695 mg, 1.58 mmol) in 1,2-dichloroethane (30 ml) and stir at roomtemperature. Add 37% Aqueous formaldehyde solution (1 ml) followed bysodium triacetoxyborohydride (0.35 g, 1.65 mmol). Stir the reactionmixture at room temperature overnight. Add saturated aqueous sodium andcollect the organic phase, dry and concentrate to 1.2 g dark oil.Dissolve in methanol (20 ml), add 2N hydrochloric acid (5 ml) and stirthe mixture at room temperature for 2 hours. Concentrate the reactionmixture and partitions between dichloromethane and 2N sodium hydroxidesolution. Collect the organic phase, dry and concentrate to a dark oil.Purify the material by flash column chromatography on florisil (eluentdichloromethane/methanol) to give 0.3 g yellow oil. Dissoyle thismaterial in ethanol (20 ml), add 2N hydrochloric acid (2 ml) andconcentrate the mixture and dry under high vacuum to give the desiredtitle compound as an orange solid 312 mg: mass Spectrum (FIA) 389 (M+1);mp: 191-193° C.

Example: 4066-Fluoro-10-{3-[2-(4-methoxy-phenyl-ethyl]-4-methyl-piperazin-1-yl}-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulenehydrochloride

Similarly prepared by using Example 405, using6-fluoro-10-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene.Mass Spectrum (FIA) 465 (M+1); mp: 191-193° C.

Example 4077-Fluoro-10-{3-[2-(3-fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulenehydrochloride

Similarly prepared by using Example 405, using7-fluoro-10-{3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene.Mass Spectrum (FIA) 389 (M+1); mp: 178-180° C.

Example 4087-Fluoro-10-{3-[2-(4-methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl{-2-methyl-4H-3-thia-4,9diaza-benzo[f]azulene

Similarly prepared by using Example 405, using7-fluoro-10-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene.Mass Spectrum (FIA) 465 (M+1); mp: 180-182° C.

Example 4102-Ethyl-7-fluoro-4,9-dihydro-3-thia-4,9-diaza-benzo[f]azulene-10-thione

By using a method similar to Example 373, using2-ethyl-7-fluoro-4,9-dihydro-3-thia-4,9-diaza-benzo[f]azulen-10-onegives the title compound: Mass spectrum M=278.

Example 4112-Ethyl-7-fluoro-10-{3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-4H-3-thia-4,9-diaza-benzo[f]azulene

Similarly prepared using Example 401, using2-ethyl-7-fluoro-4,9-dihydro-3-thia-4,9-diaza-benzo[f]azulene-10-thioneto give the title compound: Mass spectrum M+H=453 for free base.

Example 4122-Ethyl-7-fluoro-10-{3-[2-(3-fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-4H-3-thia-4,9-diaza-benzo[f]azulenehydrochloride

Similarly prepared using Example 405, using2-ethyl-7-fluoro-10-{3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-4H-3-thia-4,9-diaza-benzo[f]azulene.Mass spectrum M+H=467 for free base. ¹H NMR (d6-DMSO); 11.73 (bs, 1H),9.15 (bs, 1H), 7.35 (m, 1H), 7.05 (m, 6H), 6.66 (bs,1H), 3.66 (m, 8H),2.87 (m, 3H), 2.68 (m, 3H), 2.33 (m,1H), 1.91 (m, 1H), 1.18 (m, 3H).

Example 4132-Ethyl-7-fluoro-10-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-4H-3-thia-4,9-diaza-benzo[f]azulene

Similarly prepared using Example 401, using2-ethyl-7-fluoro-4,9-dihydro-3-thia-4,9-diaza-benzo[f]azulene-10-thioneto give the title compound: Mass spectrum M+H=465 for free base.

Example 4142-Ethyl-7-fluoro-10-{3-[2-(4-methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-4H-3-thia-4,9-diaza-benzo[f]azulene

Similarly prepared using Example 405, using2-ethyl-7-fluoro-10-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-4H-3-thia-4,9-diaza-benzo[f]azulene:Mass Spectrum; M+H=479 for free base, ¹H NMR (d6-DMSO); 11.62(bs,1H),9.19(bs,1H), 7.11(bs,3H), 6.99(bs,1H), 6.86(m,4H), 6.69(bs,1H),3.73(s,3H), 3.63(bs,1H), 3.41(bs,2H), 3.38(q,2H,J=7.2 Hz), 3.17(s,1H),2.85 (m,5H), 2.71(m,4H), 2.27(bs), 1.91(bs), 1.19(t, 3H J 7.3 Hz).

Example 415 (S)-1,4-Dibenzyl-2-(2-naphthalen-1-yl-ethyl)-piperazinedihydrochloride

Combine 9-borabicyclo[3.3.1]nonane (119 mL, 59.5 mmol, 0.5 M in THF) and(S)-1,4-dibenzyl-2-vinyl-piperazine (4.35 g, 14,9 mmol) and stir atambient temperature. After 18 h, add triphenylphosphine (1.25 g, 4.76mmol), tetrakis(triphenylphosphine)palladium(0) (688 mg, 0.60 mmol), THF(5 mL) and 1-iodonaphthalene (3.26 mL, 22.3 mmol). Add 3M NaOH (12.2 mL,36.6 mmol) slowly, gas evolution occurs. Heat at reflux. After 24 h,cool to ambient temperature and concentrate under reduced pressure. Add2N NaOH (200 mL), and stir 1 h. Extract with diethyl ether. Extract thediethyl ether solution with 1N H₂SO₄ and discard the diethyl ether. Awhite residue forms.

Add 5N NaOH to the 1N H₂SO₄ extracts until pH is 12-14. Extract withdiethyl ether. Wash the diethyl ether extracts with brine, dry oversodium sulfate, filter and concentrate under reduced pressure to give900 mg of crude product.

Dissolve the white residue in methanol and methylene chloride, dry oversodium sulfate, filter and concentrate under reduced pressure to give atan foam. Slurry the foam in 5N HCl (50 mL), add methanol (50 mL) togive a homogeneous solution. Filter the white precipitate that forms togive 4.46 g (61%) of(S)-1,4-di-benzyl-2-(2-naphthalen-1-yl-ethyl)-piperazinedihydrochloride: mp 211-215° C. dec; mass spectrum (ion spray): m/z=421(M+1). Analysis calculated for C₃₀H₃₄Cl₂N₂: C, 73.01; H, 6.94; N, 5.68;Cl, 14.37. Found: C, 72.98; H, 7.27; N, 5.59; Cl, 14.06.

Example 418, Example 419, Example 420(S)-1-Benzyl-3-(2-naphthalen-1-yl-ethyl)-piperazine(S)-2-(2-Naphthalen-1-yl-ethyl)-piperazine(S)-1-benzyl-2-(2-nalphthalen-1-yl-ethyl)-piperazine

Dissolve (S)-1,4-dibenzyl-2-(2-naphthalen-1-yl-ethyl)-piperazine (3.33g, 7.92 mmol) in ethanol (100 mL). Add ammonium formate (2.99 g, 47.5mmol) and palladium (666 mg, 5 wt. % on carbon) and heat to reflux.After 6 h 30 min, filter the palladium on carbon and concentrate thefiltrate. Purify by silica gel chromatography using 2N ammonia inmethanol-methylene chloride (2.5%-10%) and 7N ammonia inmethanol-methylene chloride (20%) as the eluent to give 716 mg (38%) of(S)-2-(2-naphthalen-1-yl-ethyl)-piperazine, 1.1 g of(S)-1-benzyl-3-(2-naphthalen-1-yl-ethyl)-piperazine, and 290 mg of(S)-1-benzyl-2-(2-naphthalen-1-yl-ethyl)-piperazine.

(S)-2-(2-Naphthalen-1-yl-ethyl)-piperazine: mass spectrum (ion spray):m/z=241 (M+1). ¹H NMR (DMSO-d₆, D₂O): δ 8.07 (d, 1H), 7.91 (d, 1H), 7.76(d, 1H), 7.58-7.46 (m, 2H), 7.41 (dd, 1H), 7.36 (br d, 1H), 3.19-2.94(m, 2H), 2.89-2.46 (m, 6H), 2.25 (dd, 1H), 1.60 (dd, 2H).

(S)-1-Benzyl-2-(2-naphthalen-1-yl-ethyl)-piperazine: mass spectrum (ionspray): m/z=331 (M+1). ¹H NMR (DMSO-d₆, D₂O): δ 8.03 (d, 1H), 7.91 (d,1H), 7.76 (d, 1H), 7.57-7.47 (m, 2H), 7.44-7.18 (m, 7H), 3.90 (d, 1H),3.23 (d, 1H), 3.17-2.90 (m, 3H), 2.78-2.39 (m, 5H), 2.14-2.04 (m, 1H),1.99-1.89 (m, 2H).

(S)-1-Benzyl-3-(2-naphthalen-1-yl-ethyl)-piperazine: mass spectrum (ionspray): m/z=331 (M+1). ¹H NMR (DMSO-d₆): δ 8.06 (d, 1H), 7.90 (d, 1H),7.74 (d, 1H), 7.56-7.45 (m, 2H), 7.40 (dd, 1H), 7.35-7.19 (m, 6H1), 3.42(dd, 2H), 3.20-3.08 (m, 1H), 3.05-2.91 (m, 1H), 2.87-2.79 (m, 1H),2.77-2.55 (m, 4H), 1.98-1.87 (m, 1H), 1.74-1.56 (m, 3H).

Example 421 (S)-2-(2-Naphthalen-1-yl-ethyl)-piperazine

Dissolve (S)-1-benzyl-3-(2-naphthalen-1-yl-ethyl)-piperazine (1.07 g,3.03 mmol) in ethanol (10 mL). Add ammonium formate (1.2 g, 19.0 mmol)and palladium hydroxide (200 mg, 20 wt. % on carbon) and heat to reflux.After 7 h, filter the palladium hydroxide and concentrate the filtrate.Combine with Example 422 and purify.

Example 422 (S)-2-(2-Naphthalen-1-yl-ethyl)-piperazine

Dissolve (S)-1-benzyl-2-(2-naphthalen-1-yl-ethyl)-piperazine (280 mg,0.85 mmol) in ethanol (5 mL). Add ammonium formate (320 mg, 5.1 mmol)and palladium hydroxide (60 mg, 20 wt. % on carbon) and heat to reflux.After 5.5 h, filter the palladium hydroxide and concentrate thefiltrate. Combine with Example 421 and purify by silica gelchromatography using 2N ammonia in methanol-methylene chloride (5%) and7N ammonia in methanol-methylene chloride (20%) as the eluent to give750 mg (81%) of the title compound: mass spectrum (ion spray): m/z=241(M+1). ¹H NMR (DMSO-d₆): 8.08 (d, 1H), 7.91 (d, 1H), 7.76 (d, 1H),7.59-7.32 (m, 4H), 3.53 (br s, 2H), 3.22-3.09 (m, 1H), 3.08-2.98 (m,1H), 2.98-2.73 (m, 3H), 2.71-2.53 (m, 3H), 2.31 (dd, 1H), 1.71-1.57 (m,2H).

Example 423(S)-2-Methyl-10-[3-(2-naphthalen-1-yl-ethyl)-piperazin-1-yl]-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine (S)-2-(2-naphthalen-1-yl-ethyl)-piperazine (686 mg, 2.85 mmol),2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine (654 mg, 2.85mmol), toluene (5.7 mL), DMSO (1.4 mL) and glacial acetic acid (0.5 mL).Add N-ethyldiisopropylamine (2.0 mL). Heat at 105° C. After 48 h, coolto ambient temperature and dilute with ethyl acetate and water. Extractwith ethyl acetate. Wash the extracts with water and brine, dry oversodium sulfate, filter and concentrate the filtrate. Purify by silicagel chromatography using 2N ammonia in methanol-methylene chloride(0.5%-5%) as the eluent to give 183 mg. Purify again by radial silicagel chromatography using a 2 mm plate and 2N ammonia inmethanol-methylene chloride (1%-2%) as the eluent to give 60 mg (5%) ofthe title compound: mass spectrum (ion spray): m/z=453 (M+1), 451 (M−1).Analysis calculated for C₂₈H₂₈N₄S.0.2H₂O: C, 73.71; H, 6.27; N, 12.28.Found: C, 73.37; H, 6.19; N, 12.00.

Example 424(S)-2-Methyl-10-[3-(2-naphtbalen-1-yl-ethyl)-piperazin-1-yl]-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine (S)-2-(2-naphthalen-1-yl-ethyl)-piperazine (720 mg, 3.0 mmol),2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine (686 mg, 3.0mmol), toluene (6 mL), DMSO (1.5 mL) and glacial acetic acid (1 drop).Heat at 105° C. After 48 h, cool to ambient temperature and dilute withethyl acetate and water. Extract with ethyl acetate. Wash the extractswith water and brine, dry over sodium sulfate, filter and concentratethe filtrate. Purify by silica gel chromatography using 2N ammonia inmethanol-methylene chloride (2.5%-3%) as the eluent to give 290 mg(21%)of the title compound: mass spectrum (ion spray): m/z=453 (M+1),451 (M−1).

Example 425(S)-2-Methyl-10-[4-methyl-3-(2-naphthalen-1-yl-ethyl)-piperazin-1-yl]-4H-3-thia-4,9-diaza-benzo[f]azulene

Add formaldehyde (56 μL, 0.70 mmol, 37% in water) to a solution of(S)-2-methyl-10-[3-(2-naphthalen-1-yl-ethyl)-piperazin-1-yl]-4H-3-thia-4,9-diaza-benzo[f]azulene(290 mg, 0.64 mmol) in methylene chloride (20 mL). Stir 15 min atambient temperature. Add sodium triacetoxyborohydride (204 mg, 0.96mmol) and stir 30 min at ambient temperature. Dilute with saturatedsodium bicarbonate solution and extract with methylene chloride. Dry theextracts with sodium sulfate, filter and concentrate the filtrate.Purify by radial silica gel chromatography using a 2 mm plate and 2Nammonia in methanol-methylene chloride (1%-2%) as the eluent to give 290mg (97%) of the title compound: mass spectrum (ion spray): m/z=467(M+1), 465 (M−1). HR-MS calculated for C₂₉H₃₁N₄S: 467.2269. Found467.2278. HPLC: Symmetry C₁₈ column (3.5 μm, 4.6×50 mm). Gradient 5% to90% solvent B in 7 min. Solvent A was 0.1% (v/v) TFA in water andsolvent B was acetonitrile. Retention time 5.7 min; 100% pure.

Example 426 (S)-1,4-Dibenzyl-2-(2-naphtbalen-2-yl-ethyl)-piperazinedihydrochloride

Combine 9-borabicyclo[3.3.1]nonane (163.6 mL, 81.8 mmol, 0.5 M in THF)and (S)-1,4-dibenzyl-2-vinyl-piperazine (5.98 g, 20.4 mmol) and stir atambient temperature. After 24 h, add triphenylphosphine (1.72 g, 6.54mmol), tetrakis(triphenylphosphine)palladium(0) (945 mg, 0.82 mmol) and2-bromonaphthalene (6.35 g, 30.7 mmol). Add 3M NaOH (16.8 mL, 50.4 mmol)slowly, gas evolution occurs. Heat at reflux. After 24 h, cool toambient temperature and concentrate under reduced pressure. Add 2.5NNaOH (200 mL), and stir 30 min. Extract with diethyl ether. Concentratethe diethyl ether extracts and dissolve the residue in 5N HCl (200 mL).Stir 30 min at ambient temperature. Extract with diethyl ether. Filterthe precipitate that forms during the extraction. Slurry the precipitatein methanol, make basic with 5N NaOH, extract with diethyl ether, dryover sodium sulfate, filter and concentrate. Crystallize the residuefrom ethanol to give 5.9 g (69%) of the title compound: mp 85-8° C.;mass spectrum (ion spray): m/z=421 (M+1).

Example 427 (S)-2-(2-Naphthalen-2-yl-ethyl)-piperazine

Dissolve (S)-1,4-dibenzyl-2-(2-naphthalen-2-yl-ethyl)-piperazine (6.53g, 15.5 mmol) in ethanol (80 mL). Add ammonium formate (5.9 g, 93.6mmol) and palladium hydroxide (1.5 g, 20 wt. % on carbon) and heat toreflux. After 8.5 h, cool and stir at ambient temperature 18 h. Filterthe palladium hydroxide and concentrate the filtrate. Purify by silicagel chromatography using 7N ammonia in methanol-methylene chloride(2.5%-10%) as the eluent to give 2.86 g (77%) of the title compound: mp151-4° C.; mass spectrum (ion spray): m/z=241 (M+1).

Example 428(S)-2-Methyl-10-[3-(2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine (S)-2-(2-naphthalen-2-yl-ethyl)-piperazine (854 mg, 3.72 mmol),2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine (895 mg, 3.72mmol) and 1-methyl-2-pyrrolidinone (8 mL). Heat at reflux. After 5 h,cool to ambient temperature and dilute with ethyl acetate and water.Extract with ethyl acetate. Wash the extracts with water and brine, dryover sodium sulfate, filter and concentrate the filtrate. Purify bysilica gel chromatography using 2N ammonia in methanol-methylenechloride (2.5%) as the eluent to give 576 mg (34%) of the titlecompound: mass spectrum (ion spray): m/z=453 (M+1), 451 (M−1). HR-MScalculated for C₂₈H₂₉N₄S: 453.2113. Found 453.2116. HPLC: Symmetry C₁₈column (3.5 μm, 4.6×50 mm). Gradient 5% to 90% solvent B in 7 min.Solvent A was 0.1% (v/v) TFA in water and solvent B was acetonitrile.Retention time 5.7 min; 100% pure.

Example 429(S)-2-Methyl-10-[4-methyl-3-(2-naphthalen-2-yl-ethyl-)piperazin-1-yl]-4H-3-thia-4,9-diaza-benzo[f]azulene

Add formaldehyde (101 μL, 1.28 mmol, 37% in water) to a solution of(S)-2-methyl-10-[3-(2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-4H-3-thia-4,9-diaza-benzo[f]azulene(525 mg, 1.16 mmol) in methylene chloride (20 mL). Stir 15 min atambient temperature. Add sodium triacetoxyborohydride (369 mg, 1.7 mmol)and stir 1 h at ambient temperature. Dilute with saturated sodiumbicarbonate solution and extract with methylene chloride. Dry theextracts with sodium sulfate, filter and concentrate the filtrate.Purify by silica gel chromatography using 2N ammonia inmethanol-methylene chloride (2.5%) as the eluent to give 550 mg (100%)of the title compound: mass spectrum (ion spray): m/z=467 (M+1), 465(M−1). HPLC: Symmetry C₁₈ column (3.5 μm, 4.6×50 mm). Gradient 5% to 90%solvent B in 7 min. Solvent A was 0.1% (v/v) TFA in water and solvent Bwas acetonitrile. Retention time 5.7 min; 100% pure.

Example 430(S)-2-Methyl-10-[4-methyl-3-(2-naphthalen-2-yl-ethyl)-piperazin-1-yl]-4H-3-thia-4,9-diaza-benzo[f]azulenedihydrochloride

Crystallize the dihydrochloride salt from ethyl acetate and ethanol togive the title compound: mp 209° C. dec. Mass spectrum (ion spray):m/z=467 (M+1), 465 (M−1). Analysis calculated for C₂₉H₃₂Cl₂N₄S: C,64.56; H, 5.98; N, 10.38. Found: C, 64.18; H, 5.74; N, 10.28. HR-MScalculated for C₂₉H₃₁N₄S: 467.2269. Found 467.2243. HPLC: Symmetry C₁₈column (3.5 μm, 4.6×50 mm). Gradient 5% to 90% solvent B in 7 min.Solvent A was 0.1% (v/v) TFA in water and solvent B was acetonitrile.Retention time 5.7 min; 100% pure.

Example 431 (S)-1,4-Dibenzyl-2-(2-furan-3-yl-ethyl-piperazine

Combine 9-borabicyclo[3.3.1]nonane (165.8 mL, 82.9 mmol, 0.5 M in THF)and (S)-1,4-dibenzyl-2-vinyl-piperazine (6.06 g, 20.7 mmol) and stir atambient temperature. After 24 h, add triphenylphosphine (1.74 g, 6.6mmol), tetrakis(triphenylphosphine) palladium(0) (958 mg, 0.83 mmol) and3-bromofuran (2.8 mL, 31.1 mmol). Add 3M NaOH (17.0 mL, 51.0 mmol)slowly, gas evolution occurs. Heat at reflux. After 24 h, addtetrakis(triphenylphosphine) palladium(0) (958 mg, 0.83 mmol). After 48h, cool to ambient temperature and concentrate under reduced pressure.Add 2.5N NaOH (200 mL), and stir 30 min. Extract with diethyl ether.Filter the precipitate and discard. Extract the diethyl ether extractswith 1N sulfuric acid. Make basic with SN sodium hydroxide and extractwith diethyl ether, dry over sodium sulfate, filter and concentrate.Purify by silica gel chromatography using ethyl acetate/hexanes (10%) asthe eluent to give 2.4 g of a mixture of the title compound and(S)-1,4-dibenzyl-2-ethyl-piperazine: mass spectrum (ion spray): m/z=361(M+1, (S)-1,4-dibenzyl-2-(2-furan-3-yl-ethyl)-piperazine), m/z=295 (M+1,(S)-1,4dibenzyl-2-ethyl-piperazine).

Example 432 (S)-2-(2-Furan-3-1-ethyl)-piperazine

Dissolve a mixture of (S)-1,4-dibenzyl-2-(2-furan-3-yl-ethyl)-piperazineand (S)-1,4-dibenzyl-2-ethyl-piperazine (2.29 g, 6.35 mmol) in1,2-dichloroethane (10 mL). Cool on an ice bath and add 1-chloroethylchloroformate (2.06 ml, 19.1 mmol) dropwise. Remove ice bath and heat to83° C. for 5.5 h. Concentrate the reaction, dissolve the residue inmethanol (50 mL) and heat to reflux for 2 h. Cool to ambient temperatureand stir 18 h. Filter and concentrate to a solid. Purify by silica gelchromatography using 7N ammonia in methanol-methylene chloride(2.5%-10%) as the eluent to give 330 mg (29%) of the title compound: mp112-4° C. Mass spectrum (ion spray): m/z=181 (M+1).

Example 433 (S)-2-(2-Furan-3-yl-ethyl)-piperazine

Dissolve (S)-1,4-dibenzyl-2-(2-furan-3-yl-ethyl)-piperazine (810 mg,2.25 mmol) in ethanol (5 mL). Add ammonium formate (850 mg, 13.5 mmol)and palladium (100 mg, 5 wt. % on carbon) and heat to reflux. After 3.5h, filter the palladium and concentrate the filtrate. Purify by silicagel chromatography using 7N ammonia in methanol-methylene chloride (5%)as the eluent to give 175 mg (43%) of the title compound: mass spectrum(ion spray): m/z=181 (M+1). Analysis calculated for C₁₀H₁₆N₂O: C, 66.63;H, 8.95; N, 11.54. Found: C, 66.53; H, 8.92; N, 11.14.

Example 434(S)-10-[3-(2-Furan-3-yl-ethyl)-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Combine (S)-2-(2-furan-3-yl-ethyl)-piperazine (550 mg, 3.05 mmol),2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine (700 mg, 3.05mmol), toluene (6 mL) and DMSO (1.5 mL). Heat at 100° C. After 48 h,cool to ambient temperature and dilute with ethyl acetate. Filter thesolids and dilute the filtrate with water. Extract with ethyl acetate.Wash the extracts with water and brine, dry over sodium sulfate, filterand concentrate the filtrate. Purify by silica gel chromatography using2N ammonia in methanol-methylene chloride (2.5%) as the eluent to give282 mg (24%) of the title compound: mass spectrum (ion spray): m/z=393(M+1), 391 (M-1). HR-MS calculated for C₂₂H₂₅N₄OS: 393.1749. Found393.1742. HPLC: Symmetry C₁₈ column (3.5 μm, 4.6×50 mm). Gradient 5% to90% solvent B in 7 min. Solvent A was 0.1% (v/v) TFA in water andsolvent B was acetonitrile. Retention time 5.4 min; 100% pure.

Example 435(S)-10-[3-(2-Furan-3-yl-ethyl)-4-methyl-piperazin-1-yll-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene

Add formaldehyde (49 μL, 0.61 mmol, 37% in water) to a solution of(S)-10-[3-(2-furan-3-yl-ethyl)-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene(219 mg, 0.56 mmol) in methylene chloride (20 mL). Stir 15 min atambient temperature. Add sodium triacetoxyborohydride (177 mg, 0.56mmol) and stir 1 h at ambient temperature. Dilute with saturated sodiumbicarbonate solution and extract with methylene chloride. Dry theextracts with sodium sulfate, filter and concentrate the filtrate.Purify by radial silica gel chromatography using a 2 mm plate and 2Nammonia in methanol-methylene chloride (1%-2.5%) as the eluent to give179 mg (79%) of the title compound: mass spectrum (ion spray): m/z=407(M+1), 405 (M−1). BPLC: Symmetry C₁₈ column (3.5 μm, 4.6×50 mm).Gradient 5% to 90% solvent B in 7 min. Solvent A was 0.1% (v/v) TFA inwater and solvent B was acetonitrile. Retention time 5.4 min; 100% pure;

Example 436(S)-10-[3-(2-Furan-3-yl-ethyl)-4-methyl-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzor[f]azulenedihydrochloride

Crystallize the dihydrochloride salt from ethyl acetate and ethanol togive the title compound: mp 198° C. dec. Mass spectrum (ion spray):m/z=407 (M+1), 405 (M−1). Analysis calculated for C₂₃H₂₈Cl₂N₄OS.0.3H₂O:C, 56.97; H, 5.95; N, 11.56. Found: C, 56.73; H, 5.69; N, 11.48. HR-MScalculated for C₂₃H₂₇N₄OS: 407.1906. Found 407.1892. HPLC: Symmetry Ciscolumn (3.5 μm, 4.6×50 mm). Gradient 5% to 90% solvent B in 7 min.Solvent A was 0.1% (v/v) TFA in water and solvent B was acetonitrile.Retention time 5.3 min; 100% pure.

Example 437 (S)-1,4-Dibenzyl-2-(2-thiophen-3-yl-ethyl)-piperazine

Combine 9-borabicyclo[3.3.1]nonane (54.7 mL, 27.4 mmol, 0.5 M in THF)and (S)-1,4-dibenzyl-2-vinyl-piperazine (2.0 g, 6.84 mmol) and stir atambient temperature. After 24 h, add triphenylphosphine (574 mg, 2.2mmol), tetrakis(triphenylphosphine) palladium(0) (316 mg, 0.27 mmol) and3-iodothiophene (1.93 g, 9.2 mmol). Add 3M NaOH (5.6 mL, 16.8 mmol)slowly, gas evolution occurs. Heat at reflux. After 48 h, cool toambient temperature, add 5N HCl (12 mL), and stir 1 h. Extract withethyl acetate and wash the extracts with 1N NaOH, water, brine, dry oversodium sulfate, filter and concentrate. Purify by silica gelchromatography using ethyl acetate/hexanes (10%) as the eluent to give2.38 g of the title compound as an adduct of 9-BBN: mass spectrum (ionspray): m/z=377 (M+1).

Example 438 (S)-2-(2-Thiophen-3-yl-ethyl)-piperazine

Dissolve (S)-1,4-dibenzyl-2-(2-thiophen-3-yl-ethyl)-piperazine (1.17 g,3.1 mmol) and (S)-1,4-dibenzyl-2-(2-thiophen-2-yl-ethyl)-piperazine (230mg, 0.61 mmol) in 1,2-dichloroethane (10 mL). Add 1-chloroethylchloroformate (2.0 ml, 18.5 mmol) and heat to 80° C. for 18 h.Concentrate the reaction, dissolve the residue in methanol and heat toreflux for 2 h. Concentrate to an oil. Purify by silica gelchromatography using 2N ammonia in methanol-methylene chloride (10%)then 7N ammonia in methanol-methylene chloride (10%) as the eluent togive 400 mg (55%) of a 6:1 mixture of the title compound to(S)-2-(2-thiophen-2-yl-ethyl)-piperazine: mass spectrum (ion spray):m/z=197 (M+1).

Example 439(S)-2-Methyl-10-[3-(2-thiophen-3-yl-ethyl)-piperazin-1-yl]-4H-3-thia-4,9-diaza-benzo[f]azulene

Add methyl trifluoromethanesulfonate (241 μL, 2.13 mmol) to a 0° C.slurry of2-methyl-4,9-dihydro-3-thia-4,9-diaza-benzo[f]azulene-10-thione (437 mg,1.77 mmol) in dichloromethane (5 mL). Stir 2 h at 0° C. then warm toambient temperature and stir 16 h. Concentrate the reaction to an orangepowder. Add a 6:1 mixture of (S)-2-(2-thiophen-3-yl-ethyl)-piperazineand (S)-2-(2-thiophen-2-yl-ethyl)-piperazine (346 mg, 1.76 mmol) andpyridine (5 mL). Heat to reflux for 7.5 h and stir at ambienttemperature for 18 h. Concentrate the reaction, dissolve the residue inmethanol-dichloromethane, apply to a SCX column. Wash the column withmethanol-dichloromethane to remove impurities then elute the productwith 2N ammonia in methanol-methanol (10%). Concentrate and purify bysilica gel chromatography using 2N ammonia in methanol-methylenechloride (1%-4%) as the eluent to give 333 mg of a brown foam. Purify byradial silica gel chromatography using a 4 mm plate and 1%isopropylamnine in tetrahydrofuran-hexanes (10%-20%) as the eluent togive 218 mg (30%) of the title compound: mass spectrum (ion spray):m/z=409 (M+1), 407 (M −1). HR-MS calculated for C₂₂H₂₅N₄S₂: 409.1521.Found 409.1540. ¹H NMR (DMSO-d₆): δ 7.56 (s, 1H), 7.43 (dd, 1H), 7.13(s, 1H), 6.99 (d, 1H), 6.87-6.74 (m, 3H), 6.67 (d, 1H), 6.31 (s, 1H),3.88 (br d, 1H), 3.76 (br d, 1H), 2.88 (br d, 1H), 2.80-2.53 (m, 5H),2.45-2.38 (m, 1H), 2.27 (s, 3H), 1.61 (dd, 2H).

Example 440(S)-2-Methyl-10-[4-methyl-3-(2-thiophen-3-yl-ethyl)-piperazin-1-yl]-4H-3-thia-4,9-diaza-benzo[f]azulenedihydrochloride

Add formaldehyde (45 μL, 0.56 mmol, 37% in water) to a solution of(S)-2-methyl-10-[3-(2-thiophen-3-yl-ethyl)-piperazin-1-yl]-4H-3-thia-4,9-diaza-benzo[f]azulene(210 mg, 0.51 mmol) in methylene chloride (6 mL). Stir 15 min at ambienttemperature. Add sodium triacetoxyborohydride (163 mg, 0.77 mmol) andstir 2h at ambient temperature. Dilute with saturated sodium bicarbonatesolution and extract with methylene chloride. Dry the extracts withsodium sulfate, filter and concentrate the filtrate. Purify by radialsilica gel chromatography using a 2 mm plate and 2N ammonia inmethanol-methylene chloride (2%) as the eluent to give 127 mg (59%) ofthe free base of the title compound. Crystallize the dihydrochloridesalt from ethyl acetate and ethanol to give the title compound: massspectrum (ion spray): m/z=423 (M+1), 421 (M−1). Analysis calculated forC₂₃H₂₈Cl₂N₄S₂.0.2HCl.0.3H₂O: C, 54.35; H, 5.71; N, 11.01; Cl, 15.35.Found: C, 54.10; H, 5.34; N, 10.99; Cl, 15.00. HR-MS calculated forC₂₃H₂₇N₄S₂423.1677. Found 423.1656.

By the method of Example 59, the following compounds were prepared andisolated as the free base:

No. R′ Data 441 CH₂Ph ¹H NMR(CDCl₃)δ1.19(d, 6H), 2.58-3.04(m, 8H),3.98(m, 1H), 4.09(m, 1H), 4.97(s, 1H), 6.24(s, 1H), 6.60(d, 1H), 6.87(t,1H), 6.97(t, 1H), 7.02(d, 1H), 7.18-7.36(m, 5H); MS (APCI)m/z(relintensity)417(100). Product is yellow powder. 442 CH₂CH₂Ph ¹HNMR(CDCl₃)δ1.23(d, 6H), 1.65-1.82(m, 3H), 2.58-2.97(m, 7H), 3.05(m, 1H),3.99(m, 1H), 4.11(m, 1H), 4.98(s, 1H), 6.31(s, 1H), 6.60(d, 1H), 6.87(t,1H), 6.97(t, 1H), 7.04(d, 1H), 7.20-7.32(m, 5H); MS(APCI)m/z(relintensity)431(100). 10 mg of product. 443 CH₂(2-OCH₃)Ph mp 85-97° C.; ¹HNMR(CDCl₃)δ1.18(d, 3H), 1.20(d, 3H), 2.76-2.61(m, 2H), 2.92-2.79(m, 3H),3.11-2.95(m, 3H), 3.82(s, 3H), 4.05-3.96(m, 2H), 4.98(s, 1H), 6.24(s,1H), 6.60(d, 1H), 6.91-6.84(m, 3H), 6.96(ddd, 1H), 7.02(d, 1H), 7.17(d,1H), 7.21(ddd, 1H); MS(APCI)m/z(rel intensity)447.3(100). 22% yield.

By the method of Example 90, the following compounds were prepared andisolated as the free base and the (S) isomer:

No. R′ Data 444 CH₂CH₂Ph ¹H NMR(CDCl₃)δ1.24(d, 6H), 1.75(septet, 1H),1.93-2.03(m, 2H), 2.21(m, 1H), 2.35 (s, 1H), 2.38(m, 1H), 2.58(m, 1H),2.74(m, 1H), 2.88(m, 1H), 2.96(m, 1H), 3.15(ddd, 1H), 3.93(m, 1H),4.06(m, 1H), 4.98(s, 1H), 6.34(s, 1H), 6.61(d, 1H), 6.88(t, 1H), 6.98(t,1H), 7.05(d, 1H), 7.17-7.32(m, 5H); MS (APCI)m/z(rel intensity)445(100).220 mg of product. 444a CH₂Ph ¹H NMR(CDCl₃)δ1.11(d, 3H), 1.12(d, 3H),2.40-2.49(m, 3H), 2.50(s, 3H), 2.77(septet, 1H), 2.85(m, 1H), 2.90(ddd,1H), 3.16(m, 1H), 3.22(m, 1H), 3.63(m, 1H), 3.93(m, 1H), 4.92(s, 1H),6.07(s, 1H), 6.57(d, 1H), 6.85(t, 1H), 6.92-6.97(m, 2H), 7.14-7.27 (m,5H); MS(APCI)m/z(rel intensity)431 (100). 252 mg of product. 444bCH₂(2-OCH₃—Ph) mp 79-89° C.: ¹H NMR(CDCl₃)δ1.10(d, 3H), 1.12(d, 3H),2.50-2.40(m, 3H), 2.52(s, 3H), 2.77(m, 1H), 2.96-2.86(m, 2H), 3.21(d,1H), 3.24(bt, 1H), 3.61(d, 1H), 3.78(s, 3H), 3.92(bd, 1H), 4.92(s, 1H),6.07(s, 1H), 6.57(d, 1H), 6.87-6.79(m, 3H), 6.95-6.92(m, 2H), 7.07(d,1H), 7.17(ddd, 1H); MS(APCI)m/z(rel intensity)461.3(100). 93% yield.

Example 445(S)-2-tert-Butyl-10-(3-phenethyl-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene

By using a method similar to the method of Example 460, using2-tert-butyl4H-3-thia-4,9-diaza-benzo[f]azulen-10-ylamine (0.934 g, 3.44mmol) and (S)-2-phenethyl-piperazine (0.655 g, 3.44 mmol) gives 0.561 gof the title compound as a yellow solid: mp 93-96° C.; mass spectrum(ion spray): m/z=445 (M+1); Analysis for C₂₇H₃₂N₄S(0.5 H₂O): calcd: C,71.49; H, 7.33; N, 12.35; found: C, 71.27; H, 6.88; N, 12.29.

Example 446(S)-2-tert-Butyl-10-(4-methyl-3-phenethyl-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulenedihydrochloride

In a manner such as that described in Example 461, using(S)-2-tert-butyl-10-(3-phenethyl-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene(0.429 g, 0.96 mmol) gives 0.229 g of the title compound as a yellowsolid: mp 230° C.; mass spectrum (ion spray): m/z=459 (M+1); Analysisfor C₂₈H₃₆Cl₂N₄S(1.5 H₂O): calcd: C, 60.20; H, 7.04; N, 10.03; found: C,60.57; H, 7.26; N, 10.22.

Example 447 5-Amino-2-methyl-thiazole-4-carboxylic acid ethyl ester

Add acetoamidoacetate (1000 g, 5.88 mol) to a 22 L 3-necked RB flaskequipped with reflux condenser, thermometer, mechanical stirrer then addtoluene (12 L). Add to this suspension at RT Lawesson's reagent (1187 g,2.93 mol). Stir the resulting yellow slurry at 70° C. for 16 h, cool toRT. Pour the top yellow solution away from the gummy material on thebottom of the flask into a separation funnel. Add IN HCl solution (2.5L) and TBEA (2.5 L) and stir the mixture. After 15 min., combine thebi-phase solution was into the toluene solution in the funnel. Gummymaterial maybe left in the flask. Repeat the above procedure again.Separate the aqueous and wash the combine organic solution with 1N HCl(2×2.5 L). Separate the organic layer and combine the aqueous and basifywith 2N KOH solution. Add ethyl acetate (3×4 L) and extract the product.Combine the organic layer, dry over anhydrous sodium sulfate, andevaporate to give 552 g as a pale yellow solid. Dissolve the remaininggummy in methanol (1 L) and evaporate to dryness. Add MTBE (2.5 L) and1N HCl (4 L) and stir the mixture. After 15 min., separate the organiclayer and basify the aqueous with 2N KOH solution Extract the productwith ethyl acetate (2×2 L). Combine the organic layers and dry overanhydrous sodium sulfate and evaporate to give 165 g as a pale yellowsolid. (Total: 717 g, 65%). Mass spectrum (m/e): 187(M+1); ¹HNMR(300MHz, DMSO, ppm): 1.21(t, 3H), 2.38(s, 3H), 4.21(q, 2H), 7.21 (bs, 2H).¹³CNMR(75MHz, DMSO, ppm):,15.1, 19.2, 59.8, 119.3, 145.6, 161.7, 164.1.Formula: C₇H₁₀N₂O₂S.

Example 448 2-Methyl-5-(2-nitro-phenylamino)-thiazole-4-carboxylic acidethyl ester

Add a solution of ethyl 5-amino-2-methylthiazole-4-carboxylate (120 g;645 mmol) and 2-fluoronitrobenzene (68 mL; 645 mmol) indimethylsulphoxide (1 L) to a 2 L 3-necked RB flask equipped with refluxcondenser, thermometer, mechanical stirrer. Add lithium hydroxidemonohydrate (54 g; 1290 mmol) to the solution and heat at 50° C. for 3hours under nitrogen. Cool the purple solution and pour onto ice/water,allow to stir for one hour, filter and wash with water, dry at 50° C.under reduced pressure to give 190 g (96%) as an orange solid: massspectrum (m/e): 308(M+1); ¹HNMR(300 MHz, DMSO, ppm): 1.25(tr, 3H),2.56(s, 3H), 4.25(q, 2H), 7.20(m, 1H), 7.78(m, 2H), 8.20(d, 1H),11.42(s, 1H, NH). ¹³CNMR(75 MHz, DMSO, ppm): 24.4, 29.2, 71.2, 127.8,132.5, 132.8, 137.8, 146.5, 147.0, 147.5, 160.2, 161.5, 173.7. Formula:C₁₃H₁₃N₃O₄S.

Example 449 2-Methyl-5-(2-nitrophenylamino)-thiazole-4-carboxylic acidamide

Combine ethyl 2-methyl-5-(2-nitroanilino)thiazole-4-carboxylate (80 g,260 mmol) and formamide (52 mL, 1.3 mol) in DMF (200 mL) and heat to105° C. which time the yellow slurry became a dark solution. Add to thisreaction mixture at 105° C. dropwise 25% sodium methoxide in methanol(40 mL, 182.4 mmol) during 45 min period and heat to 115° C. andcontinue stir for 60 h. Cool the reaction to RT, pour into a coldsaturated NaHCO₃ solution. Stir the resulting slurry for 1 h, filter andwash the solid with DMF/H₂O (2:1). Dry in a vacuum oven, to obtain adark brown solid (62 g, 86%). Another batch starting 100 g of ethyl2-methyl-5-(2-nitroanilino)thiazole-4-carboxylate to give 82 g (90%) ofcrude product: mass spectrum (m/e): 279(M+1); ¹HNMR(300 MHz, DMSO, ppm):2.5(s, 3H), 7.05(m, 1H), 7.51(d, 1H), 7.65(m, 2H), 8.10(d, 1H), 12.18(s,1H). ¹³CNMR(75 MHz, DMSO, ppm): 19.4, 116.8, 121.7, 127.3, 129.9, 136.3,137.0, 137.8, 145.6, 151.2, 166.1. Formula: C₁₁H₁₀N₄O₃S.

Example 450 2-Methyl-5-(2-nitro-phenylamino)-thiazole-4-carbonitrile

Combine 2-methyl-5-(2-nitroanilino)thiazole-4-carboxylic acid amide (60g, 215 mmol) and toluene and add POCl₃ (40 mL, 430 mmol) and reflux thereaction mixture. After 2.5 h cool to 0° C. Add saturated NaHCO₃solution to quench the extra POCl3 (Caution!!) until the aqueous wasaround pH 8. Add ethyl acetate (2×2 L) to extract the product. Combinedorganic layer and wash with brine (2×1 L), dry over MgSO₄. and evaporateto give a reddish solid which triturated with 25% ethyl acetate inhexane to give a reddish solid (36 g). Evaporate the filtrate to halfvolume to give second batch of compound (3.2 g). Total yield (39.2 g,70%): mass spectrum (m/e): 261(M+1); ¹HNMR(300 MHz, DMSO, ppm): 2.70(s,1H), 7.02(t, 1H), 7.22(d, 1H), 7.58(t, 1H), 8.25(d, 1H), 9.78(s, 1H). ).¹³CNMR(75MHz, DMSO, ppm): 20.4, 113.1, 116.2, 118.7, 121.2 127.0, 134.9,136.6, 140.0, 148.6, 161.5. Formula: C₁₁H₈N₄O₂S

Example 451 2-Methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylaminehydrochloride

Combine a suspension of 2-methyl-5-(2-nitroanilino)thiazole-4-nitrile(36 g,; 138.5 mmol) in isopropanol (400 ml) in a 2.0 liter 3-necked RBflask equipped with a reflux condenser, thermometer, magnetic stirrerbar and heat with stirring to 65° C. (orange solution obtained). Add tin(II) chloride hydrate (78.7 g; 415.4 mmol) in hydrochloric acid (400 ml;5M) and heat the resulting solution at reflux. After 2.5 h., cool thereaction to 15° C., filter the suspension, wash with isopropanol/water(2:1) and dry at 50° C. under reduced pressure to leave a yellow solid(36.7 g). Evaporate the filtrate to around 200 mL to form a yellowslurry. Filter the slurry again and dry at 50° C. under reduced pressureto leave a yellow solid (10 g). Combine the solid and suspend in 1 N HCl(700 mL) and heat to reflux for 20 min, cool to 15° C. Filter theresulting yellow slurry and dry at 50° C. under reduced pressure toleave a yellow solid (32.4 g, 88%): mass spectrum (m/e): 231(M+1);¹HNMR(300 MHz, DMSO, ppm): 2.5(s, 3H), 6.78(dd, 1H), 6.85(dd, 1H),6.98(t, 1H), 7.02(t, 1H), 8.80(s, 1H), 9.10(s, 1H), 9.98(s, 1H),10.78(s, 1H). ¹³CNMR(75 MHz, DMSO, ppm): 19.6, 120.1, 120.8, 123.6,125.8, 127.8, 129.2, 137.6, 154.4, 159.3, 160.4. Formula C₁₁H₁₁N₄S.

Example 452 Cyano-isobutyrylamino-acetic acid ethyl ester

Dilute aqueous saturated sodium bicarbonate (560 mL) with deionizedwater (700 mL). and stir the solution while adding ethylcyanoglyoxylate-2-oxime (70.0 g, 493 mmol) in portions (note: someoff-gassing and a gentle endotherm were observed). Add sodium dithionite(238 g, 1.37 mol, 2.8 eq.) in portions and stir at rt. After 2.5-3hours, during this time the reaction was monitored by TLC (EtOAc, I₂stain), saturate the solution with sodium chloride (400 g), and extractthe product CH₂Cl₂ (1×500 mL, 3×250 mL), making sure solid NaCl wasvisible (more added if necessary) during the extractions. Combine theorganic layers, dry over (MgSO₄), filter, and concentrate the filtrateto dryness in vacuo on a rotovapor at low bath temperature (30-35° C.)to afford 19.6 g (31%) crude amino-cyano-acetic acid ethyl ester whichwas used immediately in the next reaction.

Cool a solution of amino-cyano-acetic acid ethyl ester (19.0 g, 148mmol) in CH₂C₁₂ (300 mL) to 0-5° C. under N₂. Add pyridine (12.0 mL, 148mmol) followed by isobutyric anhydride (24.6 mL, 148 mmol). Allow thereaction solution to warm to rt overnight until complete by TLC (EtOAc).Wash the solution with aqueous 1N HCl, water, aq. sat'd NaHCO₃, thenbrine (150 mL each). Dry the organic layer over MgSO₄, filter, andconcentrate the filtrate to dryness in vacuo on a rotovapor to a solid.Triturate the solid with Et₂O (500 mL), filter and dry (50° C. vacuumoven) to afford 22.0 g (75%) of the title compound: ¹H NMR (300 MHz,DMSO-d₆) δ 9.05 (d, 1H, J=7.32 Hz), 5.67 (d, 1H, J=7.32 Hz), 4.25-4.13(m, 2H), 2.46 (dq, 1H, J=6.95 Hz), 1.21 (t, 3H, J=6.95 Hz), 1.03 (d, 6H,J=6.95 Hz). ¹³C NMR (75 MHz, DMSO-d₆) δ 176.51, 164.13, 115.60, 62.33,44.07, 33.29, 18.93, 18.86, 13.74. IR (CHCl₃) 3425, 3028, 2975, 2933,2905, 2874, 1757, 1687,1492, 1370, 1284, 1189 cm⁻¹. HRMS (FAB+) M/zcalculated for C₉H₁₅N₂O₃ (M+H) 199.1083 found 199.1075.

Example 453 Cyano-isobutyrylamino-acetic acid ethyl ester

Combine ethyl cyanoglyoxylate-2-oxime (20.0 g, 141 mmol) and 5% Pt/C(2.0 g, 10% wt. load) in acetic acid (120 mL) and EtOAc (60 mL) andhydrogenate under 40 psi H₂ overnight until the reaction is complete byTLC (5:1/heptane:EtOAc, I₂ stain). Carefully filtered the spent catalystusing partial vacuum through glass fiber paper, and rinse withHOAc/EtOAc without allowing the cake to dry out. Concentrate thefiltrate in vacuo on a rotovapor to an oil, leaving 25.5 g (96%) ofcrude amino-cyano-acetic acid ethyl ester as the HOAc salt. Partition aportion (13.0 g) of the HOAc salt between EtOAc (70 mL) and-water (35mL). Stir the biphasic solution and add dropwise aqueous 5N NaOH (1 6.5mL) to adjust the pH to 8.0-8.2. Separate the layers, and extract theaqueous layer with more EtOAc (3×25 mL). Combine the organic layer, dry(MgSO₄), filter, and concentrate the filtrate to dryness in vacuo on arotovapor at low bath temperature (30-35° C.) to afford 5.68 g (65%)crude amino-cyano-acetic acid ethyl ester which was used immediately inthe next reaction.

Cool a solution of crude amino-cyano-acetic acid ethyl ester (5.68 g,44.3 mmol) in CH₂Cl₂ (60 mL) to 0-5° C. under N₂. Add pyridine (3.60 mL,44.5 mmol), followed by isobutyric anhydride (7.40 mL, 44.6 mmol). Allowthe reaction solution to warm to rt overnight (18 h) until complete byTLC (3:1/EtOAc:heptane, 12 stain, co-spot needed to distinguish betweenSM and impurity). Wash the solution with aqueous 1N HCl, water, aq.sat'd NaHCO₃, then brine (50 mL each). Dry the organic layer (MgSO₄),filter, and concentrate the filtrate to dryness in vacuo on a rotovaporto a solid. Triturate the solid with Et₂O (150 mL), filter and dry (50°C. vacuum oven) to afford 4.33 g (49%) of the title compound.

Example 455 5-Amino-2-isopropyl-thiazole-4-carboxylic acid ethyl ester

Stir cyano-isobutyrylamino-acetic acid ethyl ester (139 g, 701 mmol)mechanically stir as a slurry in toluene (1.4 L) at rt under N₂. Addlawesson's reagent (170 g, 420 mmol, 0.6 eq.) in portions and heat thethick slurry to 70° C. and stir for 12 hours until complete by TLC(2:1/heptane:THF). Cool the mixture and concentrate to dryness in vacuoon a rotovapor to obtain 353 g of thick yellow oil that was partiallypurified by silica gel plug (1 Kg silica gel 60, 1.5 vol. warm2:1/THF:heptane as diluent, 2:1/heptane:THF as eluent). Combine theproduct containing filtrates and concentrate to dryness in vacuo on arotovapor to obtain 194 g of crude solid. Dissolve the solid in EtOAc(400 mL) at 50-60° C. with stirring, then allow to cool gradually to rt.Precipitate the product and was cool to 0-5° C. with stirring for 30minutes, isolate by suction filtration, rinse with cold EtOAc (2×50 mL),then dry in a vacuum oven at 50° C. to afford a first crop of 76.3 g(51%) of the title compound. Obtain a second crop of 17.6 g (12%)=fromthe filtrate after concentration in vacuo and silica gel chromatography(1 Kg silica gel 60, 2:1/heptane:THF). ¹H NMR (300 MHz, DMSO-d₆) δ 7.23(bs, 2H), 4.21 (q, 2H, J=6.95 Hz), 3.02 (dq, 1H, J=6.95 Hz), 1.27 (t,3H, J=6.95 Hz), 1.22 (d, 6H, J=6.95 Hz). ¹³C NMR (75 MHz, DMSO-d₆) δ163.72, 160.08, 156.20, 118.08, 58.99, 32.27, 22.35 (2),14.46. IR(CHCl₃) 3483, 3347, 2975,2933, 2868, 1668, 1582, 1530, 1494, 1464, 1409,1382 cm⁻¹. HRMS (ES) M/z calculated for C₉H₁₄N₂O₂S 215.0854, found215.0842.

Example 456 2-Isopropyl-5-(2-nitro-phenylamino)-thiazole-4-carboxylicacid ethyl ester

Combine a solution of 5-amino-2-isopropyl-thiazole-4-carboxylic acidethyl ester (8.71 g, 40.6 mmol) and 2-fluoronitrobenzene (4.28 mL, 40.6mmol) in DMSO (105 mL) and stir at rt under N₂ as LiOH (1.95 g, 81.4mmol, 2.0 eq.) or LiOH monohydrate (2 eq) is added in one portion. Thereaction turns dark. Heat the reaction mixture to 55° C. for 3 h untilcomplete by HPLC (Zorbax SB C18 25 cm, 60:40/ACN:0.1% TFA in water, 233nm, 1.0 mL/min). Cool to rt overnight, Cool the reaction to 0-5° C. withstirring as deionized water (315 mL) is added at such a rate to maintainthe temperature below 20° C. Precipitate the product and the reactioncolor changes from brown to rust-orange color. Stir the slurry for 3-4 hat rt, filter by vacuum and rinse with minimal 3:1/H₂O: DMSO, dry in avacuum oven at 60° C. to afford 12.4 g (91%) of the title compound as anorange solid: ¹H NMR (300 MHz, DMSO-d₆) δ 11.52 (bs, 1H), 8.23 (d, 1H,J=8.05 Hz), 7.80 (m, 2H), 7.21 (m, 1H), 4.36 (q, 2H, J=7.32 Hz, 6.95Hz), 3.23 (dq, 1H, J=6.95 Hz), 1.34 (m, 9H). ¹³C NMR (75 MHz, DMSO-d₆) δ163.22, 161.85, 149.08, 136.99, 136.37, 136.10, 126.53, 126.48, 121.94,117.05, 60.45, 32.47, 22.34(2), 14.24. IR (CHCl₃) 2976, 2932, 2867,1709, 1677, 1611, 1580, 1550, 1512, 1415, 1340 cm⁻¹. HRMS (ES) M/zcalculated for C₁₅H₁₇N₃O₄S 336.1018, found 336.1009.

Example 457 2 Isopropyl-5-(2-nitro-phenylamino)-thiazole-4-carboxylicacid amide

Stir 2-isopropyl-5-(2-nitro-phenylamino)-thiazole-4-carboxylic acidethyl ester (68.6 g, 204 mmol) at rt under N₂ as a slurry in DMF (205mL). Add formamide (32.4 mL, 816 mmol, 4.0 eq.) in one portion, and heatthe thick red slurry to 100° C.; a dark red/purple solution is formed.Add dropwise over 20-30 min, 25% NaOMe in MeOH (32.6 mL, 143 mmol, 0.7eq.) Increase the temperature 120° C. and stir the dark solution wasstirred at 120° C. overnight until complete (<2% Me ester+SM) by HPLC(Zorbax SB C18 25 cm, 60:40/ACN:0.1% TFA in water, 233 nm, 1.0 mL/min).After cooling the reaction to rt, add aqueous 5% NH₄Cl (410 mL) at sucha rate as to maintain the temperature below 35° C. with no externalcooling. Precipitate the product, cool the slurry to 0-5° C., filter byvacuum filtration and dry in a vacuum oven at 60° C. to afford 52.7 g(84% yield) crude title compound as a purple solid that was used withoutfurther purification. An aqueous workup may result in bad emulsions/slowseparations. ¹H NMR (300 MHz, DMSO-d₆) δ 12.22 (bs, 1H), 8.21 (d, 1H,J=7.69 Hz), 7.78 (m, 2H), 7.59 (bs, 1H), 7.53 (bs, 1H), 7.15 (m, 1H),3.23 (dq, 1H, J=6.95 Hz), 1.35 (d, 6H, J=6.95 Hz). ¹³C NMR (75 MHz,DMSO-d₆) δ 165.53, 161.44, 144.58, 137.12, 136.31, 135.72, 128.90,126.58, 121.08, 116.28, 32.32, 22.35(2). IR (CHCl₃) 3520, 3400, 3004,2967, 2925, 2866, 1658, 1611, 1578, 1513, 1427, 1342 cm⁻¹. HRMS(ES) M/zcalculated for C₁₃H₁₄N₄O₃S₁ 329.0684, found 329.0667.

Example 458 2-Isopropyl-5-(2-nitro-phenylamino)-thiazole-4-carbonitrile

Combine 2-isopropyl-5-(2-nitro-phenylamino)-thiazole-4-carboxylic acidamide (47.5 g, 155 mmol) and 2-dichloroethane (475 mL) and stir at rtunder N₂ as a dark solution. Pour POCl₃ (14.5 mL, 155 mmol) into thesolution, and heat the reaction to reflux (80-83° C.) for 2-3 h untilcomplete by HPLC (Zorbax SB C18 25 cm, 60:40/ACN:0.1% TFA in water, 233nm, 1.0 L/mmin). Coolthe reaction to rt, cool further to 0-5° C. Adjustthe pH to 8-9 by adding aqueous 2N NaOH (275 mL) at such a rate tomaintain the temperature below 20° C. Separate the layers, extract theaqueous layer with CH₂Cl₂ (2×100 mL). Combine the organic layer, washwith brine (2×100 mL), dry (MgSO₄), filter, and concentrate the filtratein vacuo to a dark oil/solid residue (40 g). Purify the crude product bysilica gel chromatography (1200 g silica gel 60, CH₂Cl₂) to afford 29.4g (66%) of the title compound as a red solid: ¹H NMR (300 MHz, DMSO-d₆)δ 9.78 (bs, 1h), 8.15 (dd, 1H, J=6.95 Hz, 1.46 Hz), 7.67 (dt, 1H, J=7.32Hz, 1.46 Hz), 7.26 (dd, 1H, J=7.32 Hz, 1.10 Hz), 7.15 (dt, 1H, J=6.95Hz, 1.10 Hz), 3.26 (dq, 1H, J=6.95 Hz), 1.33 (d, 6H, J=6.95 Hz). ¹³C NMR(75 MHz, DMSO-d₆) δ 171.85, 150.83, 139.10, 136.22, 136.00, 126.05,121.41, 118.64, 116.09, 113.73, 33.01, 22.07(2). IR (CHCl₃) 3311, 3021,2970, 2928, 2868, 2223, 1613, 1583, 1518, 1492, 1448, 1403, 1341 cm⁻¹.HRMS (ES) M/z calculated for C₁₃H₁₂N₄O₂S 289.0759, found 289.0744.

Example 459 2-Isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylaminehydrochloride

Combine 2-isopropyl-5-(2-nitro-phenylamino)-thiazole-4-carbonitrle (35.1g, 122 mmol) and IPA (525 mL) stir under N₂ and heat to 60° C. todissolve. Add a solution of SnCl₂ (70.0 g, 369 mmol, 3.0 eq.) in aqueous5M HCl (525 mL) dropwise over 30 min. Heat the reaction mixture atreflux (80-85° C.) for 1 h until complete by HPLC (Zorbax SB C18 25 cm,60:40/ACN:0.1% TFA in water, 233 nn, 1.0 mL/min). Cooling the reactionto 50° C. Remove most of the solvent in vacuo. Treat the aqueous solidresidue (188 g) with IPA (500 mL) and heat to 60-70° C. for a fewminutes to form a homogenous slurry. Cool the slurry to rt, then 0-5° C.for 1-2 h. Isolate the product by vacuum filtration and dry in a vacuumoven at 60° C. to afford 45.9 g (128%) of crude product that was heavilycontaminated with residual tin. Suspent the crude product in aqueous 1NHCl (2.25 L) and heat to reflux (95° C.) for 1 h, during which time mostof the solids dissolve. Cool to rt, isolate the product by vacuumfiltration, rinse with aqueous 1N HCl, and dry in a vacuum oven at 70°C. to afford 34.5 g (97%) of the title compound as a yellow/orangesolid. Analytical analysis: Sn (9.0%), H₂O (1.2%). ¹H NMR (300 MHz,DMSO-d₆) δ 10.96 (bs, 1H), 10.15 (bs, 1H), 8.94 (bs, 2H), 7.10-6.95 (m,2H), 6.93-6.82 (m, 2H), 3.10 (dq, 1H, J=6.95 Hz), 1.28 (s, 3H), 1.26 (s,3H). ¹³C NMR (75 MHz, DMSO-d₆) δ 164.42, 159.24, 158.94, 137.01, 128.58,127.11, 125.09, 122.87, 120.14, 119.23, 32.41, 21.98(2). IR(KBr) 3301,3249, 2964, 1653, 1614, 1553, 1509 cm⁻¹. HRMS (ES) M/z calculated forC₁₃H₁₅N₄S 259.1017 (M⁺−Cl), found 259.1010.

Example 460(S)-2-Methyl-10-(3-phenethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulenedihydrochloride hemihydrate

Combine 2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine(0.712g, 3.09 mmol)(preparation described in Eur. Pat. Appl. EP 354781(1990)and (S)-2-phenethyl-piperazine (0.588 g, 3.09 mmol) in NMP (6.0 mL) andheat at 200° C. for 3 hours. Cool to ambient temperature and dilute withwater (75 mL). Extract with ethyl acetate to give 1.11 g. of the crudeproduct. Silica gel chromatography, eluting with methylene chloride: 2NNH₃/methanol (100:5), gives 0.756 g of the title compound as the freebase. The dihydrochloride salt precipitates in ethyl acetate as a tansolid: mp 230° C.; mass spectrum (ion spray): m/z=404 (M+1); Analysisfor C₂₃H₂₇Cl₂N₅S(0.5 H₂O): calcd: C, 56.90; H, 5.81; N, 14.43; found: C,56.61; H, 5.63; N, 14.21.

Example 461(S)-2-Methyl-10-(4-methyl-3-phenethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulenedihydrochloride hemihydrate

Combine(S)-2-methyl-10-(3-phenethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene(0.5 g,1.24 mmol) and 37% Formaldehyde solution (0.1 mL, 1.36 mmol)in1,2-dichloroethane (25 mL). Stir for 10 minutes and add sodiumtriacetoxy borohydride (0.394, 1.86 mmol). Stir an additional 30 minutesand then pour solution onto saturated Sodium bicarbonate solution.Extract with methylene chloride to give 0.52 g of the crude product.Silica gel chromatography, eluting with methylene chloride: 2NNH₃/methanol (100:3), gives 0.296 g of the title compound as the freebase. The dihydrochloride salt precipitates in ethyl acetate as a yellowsolid: mp 220° C.; mass spectrum (ion spray): m/z=418 (M+1); Analysisfor C₂₄H₂₉Cl₂N₅S(0.5 H₂O): calcd: C, 57.71; H, 6.05; N, 14.02; found: C,57.81; H, 6.08; N, 13.81.

Example 462(S)-10-(3-Benzyl-piperazin-1-yl-2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene

By a similar method to Example 460, using2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine(0.703 g, 3.0mmol) and (S)-2-benzyl-piperazine (0.538 g, 3.0 mmol) give 0.410 g ofthe title compound as a yellow solid: mp 250-252° C.; mass spectrum (ionspray): m/z=390 (M+1); Analysis for C₂₂H₂₃N₅S(0.6 H₂O): calcd: C, 66.01;H, 6.09; N, 17.49; found: C, 65.94; H, 5.66; N, 17.8 1.

Example 463(S)-10-[3-(2-Methoxy-benzyl)-piperazin-1-yl]-2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene

By a similar method to the method of Example 460, using2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine(0.687 g, 2.98mmol) and (S)-2-(2-methoxy-benzyl)-piperazine (0.615 g, 2.98 mmol) gives0.437 g of the title compound as a yellow solid: mass spectrum (ionspray): m/z=420 (M+1); Analysis for C₂₃H₂₅N₅OS(0.5 H₂O): calcd: C,64.46; H, 6.12; N, 16.34; found: C, 64.20; H, 5.77; N, 16.14.

Example 464(S)-10-{3-[2-(4-Methoxy-phenyl)-ethyl]-piperazin-1-yl}-2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene

Combine (S)-2-[2-(4-methoxy-phenyl)-ethyl]-piperazine (180 mg, 0.82mmol), 2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine (188mg, 0.82 mmol), 1-methyl-2-pyrrolidinone (5 mL). Heat at 195° C. After3.75 h, cool to ambient temperature and stir 18 h. Combine with another2.30 mmol reaction executed under same conditions. Dilute with ethylacetate and water. Extract with ethyl acetate. Wash the extracts withwater and brine, dry over sodium sulfate, filter and concentrate thefiltrate. Purify by silica gel chromatography using 2N ammonia inmethanol-methylene chloride (2.5%-4%) as the eluent to give 388 mg (29%)of the title compound: mass spectrum (ion spray): m/z=434 (M+1), 432(M−1). HR-MS calculated for C₂₄H₂₈N₅OS: 434.2015. Found 434.201 HPLC:Symmetry C₁₈ column (3.5 μm, 4.6×50 mm). Gradient 5% to 90% solvent B in7 min. Solvent A was 0.1% (v/v) TFA in water and solvent B wasacetonitrile. Retention time 5.4 min; 100% pure.

Example 465(S)-10-{3-[2-(4-Methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulenedihydrochloride

Add formaldehyde (86 μL, 1.09 mmol, 37% in water) to a solution of(S)-10-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene(430 mg, 0.99 mmol) in methylene chloride (20 mL). Stir 15 min atambient temperature. Add sodium triacetoxyborohydride (315 mg, 1.49mmol) and stir 1 h at ambient temperature. Dilute with saturated sodiumbicarbonate solution and extract with methylene chloride. Dry theextracts with sodium sulfate, filter and concentrate the filtrate.Purify by silica gel chromatography using 2N ammonia inmethanol-methylene chloride (1%-3%) as the eluent to give 400 mg (90%)of the free base of the title compound. Crystallize the dihydrochloridesalt from ethyl acetate and ethanol to give the title compound: massspectrum (ion spray): m/z=448 (M+1), 446 (M−1). Analysis calculated forC₂₅H₃₁Cl₂N₅OS.0.3H₂O: C, 57.09; H, 6.06; N, 13.32. Found: C, 56.98; H,6.17; N, 12.93. HR-MS calculated for C₂₅H₃₀N₅OS: 448.2171. Found448.2177. HPLC: Symmetry C₁₈ column (3.5 μm, 4.6×50 mm). Gradient 5% to90% solvent B in 7 min. Solvent A was 0.1% (v/v) TFA in water andsolvent B was acetonitrile. Retention time 5.4 min; 100% pure.

Example 466(S)-10-{3-[2-(4-Fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene

By a similar method to the method of Example 460, using2-methyl4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine(1.21 g, 5.25mmol) and (S)-2-[2-(4-fluoro-phenyl)-ethyl]-piperazine (1.09 g, 5.25mmol) to give 0.848 g of the title compound as a tan solid: massspectrum (ion spray): m/z=422 (M+1); Analysis for C₂₃H₂₄FN₅S(0.3 H₂O):calcd: C, 64.70; H, 5.81; N, 16.40; found: C, 64.97; H, 5.86; N, 16.15.

Example 467(S)-10-{3-[2-(3-Fluoro-phenyl)-ethyl]-piperazin-1-yl]-2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene

By using a similar method to the method of Example 460, using2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine(1.25 g, 5.42mmol) and (S)-2-[2-(3-fluoro-phenyl)-ethyl]-piperazine (1.13 g, 5.42mmol) gives 1.06 g of the title compound as a tan solid: mass spectrum(ion spray): m/z=422 (M+1); Analysis for C₂₃H₂₄FN₅S(0.2 H₂O): calcd: C,64.98; H, 5.78; N, 16.47; found: C, 65.18; H, 5.91; N, 16.17.

Example 468(S)-2-Isopropyl-10-(3-phenethyl-piperazin-1-yl)4H-3-thia-1,4,9-triaza-benzo[f]azulene

By using a similar method of Example 460, using2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine(1.47 g,5.69 mmol) and (S)-2-phenethyl-piperazine (1.08 g, 5.69 mmol) to give1.04 g of the title compound as a yellow solid: mass spectrum (ionspray): m/z=432 (M+1); Analysis for C₂₅H₂₉N₅S: calcd: C, 69.57; H, 6.77;N, 16.22; found: C, 69.40; H, 6.90; N, 15.98.

Example 469(S)-2-Isopropyl-10-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulene

By using a similar method of the method of Example 460, using2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine(1.48 g, 5.7mmol) and (S)-2-[2-(4-methoxy-phenyl)-ethyl]-piperazine (1.26 g, 5.7mmol) to give 1.01 g of the title compound as a yellow solid: massspectrum (ion spray): m/z=462 (M+1); Analysis for C₂₆H₃₁N₅OS(0.3 H₂O):calcd: C, 66.87; H, 6.82; N, 15.00; found: C, 66.58; H, 6.35; N, 14.96.

Example 470(S)-10-(3-Benzyl-piperazin-1-yl)-2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene

By using a similar method of the method of Example 460, using2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine(1.44 g, 5.5mmol) and (S)-2-benzyl-piperazine (0.983 g, 5.5 mmol) to give 0.580 g ofthe title compound as a yellow solid: mass spectrum (ion spray): m/z=418(M+1); Analysis for C₂₄H₂₇N₅S(0.2 H₂O): calcd: C, 68.44; H, 6.56; N,16.63; found: C, 68.63; H, 6.43; N, 16.74.

Example 471(S)-10-{3-[2-(3-Fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-isoproyyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene

By using a method similar to the method of Example 460, using2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-ylamine (0.566 g,2.19 mmol) and (S)-2-[2-(3-fluoro-phenyl)-ethyl]-piperazine (0.457 g,2.19 mmol) to give 0.539 g of the title compound as a solid: massspectrum (ion spray): m/z=450 (M+1); Analysis for C₂₅H₂₈FN₅S(0.2 H₂O):calcd: C, 66.26; H, 6.32; N, 15.45; found: C, 65.96; H, 6.11; N, 15.31.

Example 472(S)-10-{3-[2-(4-Fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene

Stir2-isopropyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione(0.551 g, 2.0 mmol) in dichloromethane (10.0 mL) and chilled in an icebath while adding methyl trifluoromethane sulfonate (0.27 mL, 2.4 mmol).Allow this solution to stir at ambient temperature for 16 hours.Evaporate the solvent to a gray solid. Dissolve this solid and(S)-2-[2-(4-fluoro-phenyl)-ethyl]-piperazine (0.417 g, 2.0 mmol) inpyridine (8.0 mL) and heat at 115° C. for 23 hours. After evaporation ofthe pyridine, silica gel chromatography, eluting with methylenechloride: 2N NH₃/methanol (100:5), gives 0.354 g of the title compoundas a yellow solid: mass spectrum (ion spray): m/z=450 (M+1); Analysisfor C₂₅H₂₈FN₅S(0.2 H₂O): calcd: C, 66.26; H, 6.32; N, 15.45; found: C,66.01; H, 6.15; N, 15.25.

Example 473(S)-10-(3-Benzyl-4-methyl-piperazin-1-yl)-2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulenedihydrochloride

In a manner such as that described in Example 461,(S)-10-(3-benzyl-piperazin-1-yl)-2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene(0.355 g, 0.91 mmol) gives 0.407 g of the title compound as a yellowsolid: mp 240° C.; mass spectrum (ion spray): m/z=404 (M+1); Analysisfor C₂₃H₂₇Cl₂N₅S(0.5 H₂O): calcd: C, 56.90; H, 5.81; N, 14.43; found: C,56.74; H, 5.85; N, 14.23.

Example 474(S)-10-[3-(2-Methoxy-benzyl)-4-methyl-piperazin-1-yl]-2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulenedihydrochloride

In a manner such as that described in Example 461, using(S)-10-[3-(2-methoxy-benzyl)-piperazin-1-yl]-2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene(0.388 g, 0.92 mmol) gives 0.452 g of the title compound as an orangesolid: mp 185° C.; mass spectrum (ion spray): m/z=434 (M+1); Analysisfor C₂₄H₂₉Cl₂N50S(2.1 H₂O): calcd: C, 52.96; H, 6.15; N, 12.87; found:C, 52.84; H, 5.75; N, 12.49.

Example 475(S)-2-Isopropyl-10-(4-methyl-3-phenethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulenedihydrochloride

In a manner such as that described in Example 461, using(S)-2-isopropyl-10-(3-phenethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene(0.950 g, 2.2 mmol) gives 0.686 g of the title compound as an orangesolid: mp 210° C.; mass spectrum (ion spray): m/z=446 (M+1); Analysisfor C₂₆H₃₃Cl₂N₅S(1.2 H₂O): calcd: C, 57.81; H, 6.61; N, 12.97; found: C,58.07; H, 6.55; N, 12.56.

Example 476(S)-2-Isopropyl-10-{3-[2-(4-methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulenedihydrochloride

In a manner such as that described in Example 461, using(S)-2-isopropyl-10-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulene(0.932 g, 2.0 mmol) gives 0.770 g of the title compound as a yellowsolid: mp 190° C.; mass spectrum (ion spray): m/z=476 (M+1); Analysisfor C₂₇H₃₅Cl₂N₅OS(0.2 H₂O): calcd: C, 58.73; H, 6.46; N, 12.68; found:C, 58.44; H, 6.01; N, 12.58.

Example 477(S)-10-(3-Benzyl-4-methyl-piperazin-1-yl)-2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulenedihydrochloride

In a manner such as that described in Example 461, using(S)-10-(3-benzyl-piperazin-1-yl)-2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene(0.517 g, 1.23 mmol) gives 0.491 g of the title compound as a yellowsolid: mp 235° C.; mass spectrum (ion spray): m/z=432 (M+1); Analysisfor C₂₅H₃₁Cl₂N₅S(1.0 H₂O): calcd: C, 57.46; H, 6.37; N, 13.40; found: C,57.18; H, 5.80; N, 13.39.

Example 478(S)-10-{3-[2-(4-Fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulenedihydrochloride

In a manner such as that described in Example 461, using(S)-10-{3-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene(0.776 g, 1.84 mmol) gives 0.694 g of the title compound as a yellowsolid: mp 230° C.; mass spectrum (ion spray): m/z=436 (M+1); Analysisfor C₂₄H₂8Cl₂FN₅S(0.7 H₂O): calcd. C, 55.32; H, 5.69; N, 13.44; found:C, 55.20; H, 5.63; N, 13.36.

Example 479(S)-10-{3-[2-(3-Fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-methyl-4H-3-thia-1,4,9-triaza-benzo[f]azulenedihydrochloride

In a manner such as that described in Example 461, using(S)-10-{3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-methyl4H-3-thia-1,4,9-triaza-benzo[f]azulene(0.951 g, 2.25 mmol) gives 0.841 g of the title compound as a yellowsolid: mp 230° C.; mass spectrum (ion spray): m/z=436 (M+1); Analysisfor C₂₄H₂₈Cl₂FN₅S(0.5 H₂O): calcd C, 55.70; H, 5.65; N, 13.53; found: C,55.94; H, 5.65; N, 13.37.

Example 480(S)-10-43-[2-(3-Fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl-2-isoproyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene dihydrochloride

In a manner such as that described in Example 461, using(S)-10-{3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene(0.4301 g, 0.95 mmol) gives 0.440 g of the title compound as an orangesolid: mp 180° C.; mass spectrum (ion spray): m/z=464 (M+1).

Example 481(S)-10-{3-[2-(4-Fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl]-2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulenedihydrochloride

In a manner such as that described in Example 461, using(S)-10-{3-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene(0.316 g, 0.7 mmol) gives 0.338 g of the title compound as an orangesolid: mp 228° C.; mass spectrum (ion spray): m/z=464 (M+1); Analysisfor C₂₆H₃₂Cl₂FN₅S(0.6 H₂O): calcd: C, 57.05; H, 6.11; N, 12.80; found:C, 56.72; H, 5.73; N, 12.54.

Example 482 Pentanoic acid(2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4diazepin-3-yl)-amide

Add valeryl chloride (3.92 mL, 33.0 mmol) dropwise to a solution of3-Amino-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione (5.74 g, 30.0 mmol)and triethylamine (4.60 mL, 33.0 mmol) in anhydrous dimethylformamide(123 mL) and stir. After 6 hours, concentrate under reduced pressure toa residue and reconstitute the residue in a solution ofisopropanol:chloroform (1:3, 500 mL). Stir overnight to give a solid andisolate the solid by suction filtration, washing the solid withdichloromethane. Vacuum dry the solid at ambient temperature 2 hours toafford the title compound. Wash the filtrate with a saturated aqueoussolution of sodium bicarbonate (2×200 mL), and filter the extractionmixture to remove salt formed in the wash. Separate the organic phaseand wash it with saturated aqueous sodium chloride (150 mL). Backextract the bicarbonate aqueous phase with dichloromethane. Combine allorganics, and dry (sodium sulfate), filter, and concentrate underreduced pressure to a residue. Triturate the residue in diethyl ether,filter the resulting solid, and wash it with diethyl ether; repeat 2×.Dry the solid at ambient temperature under vacuum to give the titlecompound: mass spectrum (APCI, m/e): 276 (M+1); ¹H NMR (300 MHz,DMSO-d₆): 10.68 (s, 2H), 8.23 (d, 1H, J=7.5 Hz), 7.20 (m, 4H), 4.71 (d,1H, J=7.5 Hz), 2.25 (t, 2H, J=7.5 Hz), 1.43 (m, 2H), 1.25 (m, 2H), 0.83(t, 3H, J=7.5 Hz).

Example 4832-Butyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione

Combine pentanoic acid(2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-amide (4.13g, 15.0 mmol) and Lawesson's reagent (9.10 g, 22.5 mmol) in anhydrousdichloroethane (250 mL), heat to 85° C., and stir. After 16 hours, coolto ambient temperature, collect the reaction solid by suctionfiltration, and dry the solid at ambient temperature under vacuum togive the title compound: mass spectrum (APCI, m/e): 290 (M+1); ¹H NMR(300 MHz, DMSO-d₆) 10.95 (s, 1H), 9.01 (s, 1H), 6.93 (m, 3H), 6.71 (d,1H, J=7.5 Hz), 2.68 (t, 2H, J=7.5 Hz), 1.53 (m, 2H), 1.30 (m, 2H), 0.85(t, 3H, J=7.5 Hz).

Example 484(S)-2-Butyl-10-(3-phenethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene

Add methyl trifluoromethanesulfonate (0.850 mL, 7.51 mmol) to a 0° C.solution of2-Butyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione (1.45g, 5.01 mmol) in anhydrous dichloromethane. Rinse solids into reactionwith dichloromethane and stir allowing reaction to slowly reach ambienttemperature. After an overnight period, concentrate under reducedpressure to afford crude methylated intermediate. Take 1.06 g of thisintermediates (2.0 mmol), and combine the intermediate and2-(S)-Phenethyl-piperazine (0.38 g, 2.0 mmol), with anhydrous pyridine,heat to 100° C. and stir. After an overnight period, cool to ambienttemperature and concentrate under reduced pressure to an oil (2.16 g),followed by two chromatographic purifications, eluting with a gradientof a 8% solution of 2M ammonia in methanol, in dichloromethane (0-100%in dichloromethane), gives the title compound (0.078 g). Mass spectrum(APCI+, m/e): 446 (M+1); ¹H NMR (300 MHz, DMSO-d₆), δ (ppm): 7.79 (s,1H), 7.31-7.10 (m, 5H), 6.90-6.74 (m, 3H), 6.71-6.64 (m, 1H), 4.14-3.92(br. m, 1H), 3.44-3.22 (m, 1H), 2.93-2.52 (m, 10H), 1.65-1.49 (m, 4H),1.36-1.20 (m, 2H, J=7.1 Hz), 0.82 (t, 3H, J=7.1 Hz).

Example 485(S)-2-Butyl-10-(3-phenethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulenedihydrochloride

Add a solution of acetyl chloride (0.0601 mL, 0.842 mmol) in absoluteethanol at ambient temperature to(S)-2-Butyl-10-(3-phenethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene(0.075 g, 0.17 mmol) in absolute ethanol, with added drops of methanolto solubilize the freebase, stir and concentrate under reduced pressureto give the title compound (0.078 g): Mass spectrum (ES+, m/e): 446(M+1−2HCl); exact mass spectrum (ES+, m/e, C₂₆H₃₁N₅S.2HCl): calc.446.2378 (M+1-2HCl), found 446.2397.

Example 486 (S)-2-Butyl-10-(4-methyl-3-phenethyl-piperazin-1yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene

Add sodium triacetoxyborohydride and aqueous formaldehyde (37%w/w, to asolution of(S)-2-Butyl-10-(3-phenethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene(0.50 g, 1.1 mmol) in dichloroethane (12 mL) and stir. After 5 hours,dilute with a saturated aqueous solution of sodium bicarbonate, andseparate the layers. Extract the aqueous layer with dichloromethane(3×), combine organics, and dry (sodium sulfate), filter, andconcentrate under reduced pressure to an oil (0.24 g). Purify the oil byflash chromatography, eluting with a gradient of a 5% solution of 2Mammonia in methanol, in dichloromethane (0-100% over 30 minutes), andthen with a 5% solution of 2M ammonia in methanol, in dichloromethane togive the title compound (0.19 g): Mass spectrum (APCI+, m/e): 460 (M+1);¹H NMR (300 MHz, CDCl₃), δ (ppm): 7.39-7.11 (m, 5H), 7.11-6.95 (m, 2H),6.94-6.81 (m, 1H), 6.69-6.57 (m, 1H), 5.01 (s, 1H), 4.40-3.93 (br. m,1H), 3.34-3.16 (m, 1H), 3.08-2.92 (m, 1H), 2.93-2.40 (m, 7H), 2.40-2.23(m, 4H), 2.06-1.51 (m, 4H), 1.38 (d, 2H, J=7.1 Hz), 0.90 (t, 3H, J=7.1Hz).

Example 487(S)-2-Butyl-10-(4-methyl-3-phenethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulenedihydrochloride

Add a solution of acetyl chloride (0.15 mL, 2.1 mmol) in absoluteethanol at ambient temperature to(S)-2-Butyl-10-(4-methyl-3-phenethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene(0.19 g, 0.41 mmol) in absolute ethanol, with added drops of methanol tosolubilize the freebase, and concentrate under reduced pressure givesthe title compound (0.18 g). Mass spectrum (APCI+, m/e): 460 (M+1−2HCl);exact mass spectrum (ES+, m/e, C₂₇H₃₃N₅S.2HCl): calc. 460.2535(M+1−2HCl), found 460.2556.

Example 488 Cyclopentanecarboxylic acid(2,4-Dioxo-2,3,4,5-tetrahydro-1H-benzo]b][1,4]diazapin-3-yl)-amide

Combine 3-amino-1H-1,5-benzodiazepine-2,4-(3H, 5H)-dione (7.0 g, 36.6mmol) and triethyl amine (4.07 g, 40.3 mmol) in 120 mL DMF and adddropwise cyclopentanecarbonyl chloride (5.34 g, 40.3 mmol) at RT. Afterstirring overnight, remove DMF under reduced pressure, suspend theresidue in a mixed solvent (CHCl₃/i-PrOH=3/1, 400 mL). Collect anoff-white solid via suction filtration to give the title compound. Washthe filtrate with NaHCO₃ (sat.2×100 mL) and dry with Na₂SO₄. Concentratethe the solvent to give second crop of title compound, total 9.13 g,yield 87%: ¹H NMR (300 MHz, DMSO-d₆): 10.70 (s, 2H), 8.11 (d, 1H, J=7.8Hz), 7.24-7.15 (m, 4H), 4.73 (d, 1H, J=7.5 Hz), 2.96-2.87 (m, 1H),1.74-1.45 (m, 8H).

Example 4892-cyclopentyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione

Combine cyclopentanecarboxylic acid (2,4-Dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazapin-3-yl)-amide (1.90 g,6.6 mmol) and Lawesson's reagent (4.01 g, 9.9 mmol) in 120 mL1,2-dichloroethane and heat to reflux under N₂. Cool the reaction to RT,after 4 hour, collect 1.56 g orange solid via suction filtration, yield78%. ¹H NMR (400 MHz, DMSO-d₆): 10.96 (s, 1H), 9.05 (s, 1H), 7.00-6.89(m, 3H), 6.78-6.76 (m, 1H), 3.21-3.10 (m, 1H), 2.00-1.90(m, 2H),1.7-1.55 (m, 6H).

Example 4902-Cyclopentyl-10-(4-methyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene

Combine N-methyl piperazine (0.264 g, 2.64 mmol) and2-cyclopentyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo{f}azulene-10-thione(0.205 g, 0.66 mmol) in 7 ml of pyridine, and heat to reflux over night.Cool to room temperature, remove pyridine, the residue purify on silicagel using 2N ammonia in methanol/ dichloromethane (1:10) as the eluentto give 165 mg foam, which recrystallize in methanol to give 110 mg oftitle compound: Mass spectrum (electrospray) (m/e): C₂₀H₂₅N₅S, Cacl.Mass (M): 367.18, Found: 368.18(M+1); ¹H NMR (400 MHz, CDCl₃) δ ppm:6.97-6.90 (m, 2H), 6.81 (dt, 1H, J=7.3 Hz, J=1.0 Hz), 6.55 (dd, 1H,J=7.8 Hz, J=1.5 Hz), 4.96 (br, 1H), 3.2-3.17 (m, 1H), 2.49-2.47 (m, 4H),2.28 (s, 3H), 2.03-1.97 (m, 2H), 1.71-1.55 (m, 10H).

Example 491(S)-2-Cyclopentyl-10-(3-phenethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene

Combine (S)-2-phenethyl-piperazine (0.537 g, 3.0 mmol) and2-cyclopentyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo{f}azulene-10-thione(0.451 g, 1.5 mmol) in 10 ml of pyridine, and heat to 85° C. for 20hour. Cool to room temperature, remove pyridine, the residue purify onsilica gel using 2N ammonia in methanol/dichloromethane (1:10) as theeluent to give 265 mg of title compound as yellow solid. Mass spectrum(electrospray) (m/e): C₂₇H₃₁N₅S, Cacl. Mass: 457.2; Found: 458.3 (M+1);¹H NMR (400 MHz, CDCl₃) δ ppm: 7.31-7.27 (m, 2H), 7.24-7.16 (m, 3H),7.05-6.97 (m, 2H), 6.86 (dt, 1H, J=7.8 Hz, J=1.9 Hz), 6.62 (dd, 1H,J=7.8 Hz, J=1.0 Hz), 5.00 (br, 1H), 4.25 (br, 1H), 3.25 (t, 1H, J=7.8Hz), 3.02-2.88 (m, 4H), 2.73-2.63 (m, 3H), 2.07-2.03 (m, 2H), 1.77-1.61(m, 10H).

Example 492(S)-2-Cyclopentyl-10-(3-phenethyl-4-methyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulenedihydrochloride

Combine2-cyclopentyl-10-(3-phenethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene(220 mg, 0.48 mmol), formaldehyde (37%, w/w, aq) (47 mg, 0.58 mmol) andsodium triacetoxyborohydride (152.6 mg, 0.72 mmol) in 12 mL1,2-dichloroethane and stir at RT for 4 hours. Quench the reaction byadding water, then extract with CH₂Cl₂, dry the combined organicsolvents over Na₂SO₄. The crude material purify by flash chromatographyon silica gel, gradient 100% CH₂Cl₂ to 100% mixed solvent of (15% 2Nammonia in methanol of dichloromethane) over 55 min, give 225 mg yellowfoam,2-Cyclopentyl-10-(3-phenethyl-4-methyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene.The dihydrochloric salt is form by adding 3 eq of acetyl chloride (111.4mg, 1.42 mmol) to the free base (223 mg, 0.437 mmol) in ethanol (5 mL).After removing the solvent, the residue dissolve in 15 ml mix solvent ofCH₃CN/H₂O=50/50, lyophilize overnight, afford 235 mg of orange solid.Mass spectrum (electrospray) (m/e): C₂₈H₃₃N₅S, Cacl. Mass: 471.2; Found:472.2 (M+1).

Example 493(S)-2-Cyclopentyl-10-(3-benzyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene

Using a method similar to the method of Example 491, using(S)-2-benzyl-piperazine (1.23 g, 7.0 mmol),2-cyclopentyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo{f}azulene-10-thione(0.602 g, 2.0 mmol) in 8 ml of pyridine Obtain 240 mg light brown foamof title compound. Mass spectrum (electrospray) (m/e): C₂₆H₂₉N₅S, Cacl.Mass: 443.36; Found: 444.1 (M+1); ¹H NMR (400 MHz, CDCl₃) δ ppm:7.32-7.21 (m, 5H), 7.03-6.97 (m, 2H), 6.86 (dt, 1H, J=7.8 Hz, J=1.9 Hz),6.61 (d, 1H, J=7.8 Hz), 5.00 (br, 1H), 3.21-2.90 (m, 4H), 2.78-2.72 (m,1H), 2.62-2.56 (m, 1H), 2.03-1.95 (m, 2H), 1.77-1.62 (m, 10H).

Example 494(S)-2-Cyclopentyl-10-(3-benzyl-4-methyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene,dihydrochloride

Using a method similar to the method of Example 492, using(S)-2-cyclopentyl-10-(3-benzyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene(185 g, 0.418 mmol), formaldehyde (37%, w/w, aq) (42.3 mg, 0.52 mmol)and sodium triacetoxyborohydride (132 mg, 0.63 mmol) in 5 mL1,2-dichloroethane and stir at RT for 5 hours After purification, give157 mg of free base as yellow solid: mass spectrum (electrospray) (m/e):C₂₇H₃₁N₅S, Calc. Mass: 457.23; Found: 458.1 (M+1); The dihydrochloricsalt is form by adding 3 eq of acetyl chloride (77.3 mg, 0.98 mmol) tothe free base (150 mg, 0.33 mmol) in ethanol (5 mL). After removing thesolvent, the residue dissolve in 10 ml mix solvent of CH₃CN/H₂O=50/50,lyophilize overnight, afford 176 mg of orange solid.

Example 495(S)-2-Cyclopentyl-10-{3-[2-(3-methoxy-phenyl)-ethyl]-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulene

By using a method similar to the method of Example 491, using(S)-2-(3-methoxy-phenyl)-piperazine (1.10 g, 5.0 mmol) and2-cyclopentyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo{f}azulene-10-thione(0.540 g, 1.79 mmol) in 6 ml of pyridine, and heat to 85° C. for 5 hour.After purification, give 310 mg of title compound as brown solid. Massspectrum (electrospray) (m/e): C₂₈H₃₃N₅OS, Cacl. Mass: 487.24; Found:488.1 (M+1); ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.21-7.17 (m, 1H), 7.05-6.97(m, 2H), 6.86 (dt, 1H, J=7.3 Hz, J=1.9 Hz), 6.79-6.72 (m, 3H), 6.61 (dd,1H, J=7.8 Hz, J=1.5 Hz), 5.00 (br, 1H), 4.25 (br, 1H), 3.78 (s, 3H),3.02-2.89 (m, 4H), 2.69-2.63 (m, 3H), 2.07-2.04 (m, 2H1), 1.77-1.48 (m,10M).

Example 496(S)-2-Cyclopentyl-10-{3-[2-(3-methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulene,dihydrochloride

By using the method similar to the Example 492, using(S)-2-cyclopentyl-10-{3-[2-(3-methoxy-phenyl)-ethyl]-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulene,(270 mg, 0.55 mmol), formaldehyde (37%, w/w, aq) (0.56 g, 0.69 mmol) andsodium triacetoxyborohydride (174.8 mg, 0.825 mmol) in 8 mL1,2-dichloroethane and stir at RT. After purification, give 230 mg offree base as brown oil. Mass spectrum (electrospray) (m/e): C₂₉H₃₅N₅OS,Cacl. Mass: 501.26; Found: 502.1 (M+1); ¹H NMR (400 MHz, CDCl₃) δ ppm:7.21-7.17 (m, 1H), 7.06-6.96 (m, 2H), 6.87 (dt, 1H, J=7.8 Hz, J=1.5 Hz),6.79-6.72 (m, 3H), 6.62 (dd, 1H, J=7.8 Hz, J=1.5 Hz), 5.05 (br, 1H),3.78 (s, 3H), 3.27-3.21 (m, 1H), 3.02-2.72 (m, 3H), 2.60-2.42 (m, 2H),2.38-2.28 (m, 4H), 2.12-1.83(m, 3H), 1.76-1.60 (m, 10H). Thedihydrochloric salt is form by adding 3 eq of acetyl chloride (105.8 mg,1.37 mmol) to the free base (225 mg, 0.45 mmol) in ethanol (5 mL). Afterremoving the solvent, the residue dissolve in 10 ml mix solvent ofCH₃CN/H₂O=50/50, lyophilize overnight, afford 252 mg of orange solid.

Example 497(S)-2-Cyclopentyl-10-{3-2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulene

Slowly add (S)-2-(4-methoxy-phenyl)-piperazine (440 mg, 2.0 mmol) in 5.0mL of pyridine to 2-cyclopentyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo{f}azulene-10-thione (602 mg, 2.0 mmol) in 5 ml of pyridine over 2.5 hat 85° C., then stir for 5 h at 85° C. Cool to RT, remove the solvent,the residue purified on silica gel, using gradient (dichloromethane to15% of 2N ammonia in methanol/dichloromethane), give 450 mg of titlecompound. Mass spectrum (electrospray) (m/e): C₂₈H₃₃N₅OS, Cacl. Mass:487.24; Found: 488.1 (M+1); ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.11-6.97 (m,4H), 76.89-6.81 (m, 3H), 6.63 (m, 1H), 5.02 (br, 1H), 4.25 (br, 1), 3.78(s, 3H), 3.26-3.23 (m, 1H), 2.99-2.88 (m, 41), 2.68-2.62 (m, 3H),2.10-2.03 (m, 2H), 1.76-1.16 (m, 10H).

Example 498(S)-2-Cyclopentyl-10-{3-[2-(4-methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl]-4H-3-thia-1,4,9-triaza-benzo[f]azulene,dihydrochloride

By using a method similar to the method of Example 492, using(S)-2-Cyclopentyl-10-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulene,(220 mg, 0.45 mmol), formaldehyde (37%, w/w, aq) (45.8 mg, 0.56 mmol)and sodium triacetoxyborohydride (143 mg, 0.675 mmol) in 5 mL1,2-dichloroethane and stir at RT. After purification, give 200 mg offree base as brown oil. ¹H NMR (400 MHz, CDCl₃) δ ppm: 7.11-6.97 (m,4H), 6.89-6.80 (m, 3H), 6.61 (dd, 1H, J=7.8 Hz, J=1.0 Hz), 5.02 (br,1H), 3.78 (s, 3H), 3.27-3.21 (m, 1H), 3.02-2.60 (m, 2H), 2.56-2.42 (m,2H), 2.34-2.28 (m, 5H), 2.12-2.06 (m, 2H), 1.95-1.83(m, 1H), 1.77-1.61(m, 10H). The dihydrochloric salt is form by adding 3 eq of acetylchloride (94.2 mg, 1.20 mmol) to the free base (200 mg, 0.40 mmol) inethanol (5 mL). After removing the solvent, the residue dissolve in 10ml mix solvent of CH₃CN/H₂O=50/50, lyophilize overnight, afford 223 mgof title compound as orange solid.

Example 499N-(2,4-Dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazapin-3-yl)-propionamide

Combine 3-amino-1H-1,5-benzodiazepine-2,4-(3H, 5H)-dione (5.7 g, 30.0mmol) and triethyl amine(3.33 g, 33.0 mmol) in 120 mL DMF and addpropionyl chloride (3.05 g, 33.0 mmol) dropwise at RT. After stirringovernight, remove DMF under reduced pressure, suspend the residue in amixed solvent (CHCl₃/i-PrOH=3/1, 400 mL). Collect an off-white solid viasuction filtration to give the title compound. Wash the filtrate withNaHCO₃ (sat.2×100 mL) and dry with Na₂SO₄. Concentrate the organicsolvent down to a residue, treat with ether, collect the solid as titlecompound: mass spectrum (APCI) (m/e): 248.1 (M+1). ¹H NMR (400 MHz,DMSO-d₆): 10.70 (s, 2H), 8.19 (d, 1H, J=7.2 Hz), 7.23-7.15 (m, 4H),4.73(d, 1H, J=8.0 Hz), 2.27 (q, 2H, J=8.0 Hz), 0.94 (t, 3H, J=8.0 Hz).

Example 5002-Ethyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione

CombineN-(2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazapin-3-yl)-propionamide(3.7 g, 15.0 mmol) and Lawesson's reagent (9.09 g, 22.5 mmol) in 225 mL1,2-dichloroethane, heat to reflux under N₂. After refluxing overnight,cool the reaction to RT, collect the orange solid via suctionfiltration, and dry under vacuum to obtain 3.3 g crude material. Takecrude material (1.0 g), mix with Lawesson's reagent (0.75 g) in1,2-dichloroethane (30 mL), heat to reflux overnight, cool to RT,collect the orange-red solid via suction filtration to obtain the titlecompound. Treat the remaining of the intermediate similarly (2.3 g) toobtain additional title compound: mass spectrum (electrospray) (m/e):261.8 (M+1), 260.0 (M−1); ¹H NMR (300 MHz, DMSO-d₆): 10.97 (s, 1H), 9.17(s, 1H), 7.00-6.91 (m, 3H), 6.79-6.70 (m, 1H), 2.73 (q, 2H, J=7.5 Hz),1.16 (t, 3H, J=7.5 Hz),

Example 501(S)-2-Ethyl-10-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulene

Add methyl trifluoromethanesulfonate (4.2 g, 26.0 mmol) overnight, to asuspension of 2-ethyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo{f}azulene-10-thione (3.4 g, 13.0 mmol) in 35 mL CH₂Cl₂, LC-MS showedstill had 50% of starting material, added another 0.1 mL of methyltrifluoromethanesulfonate, and heated to 35° C. for 1 h. Concentrate thereaction mixture under reduced pressure to give a red-brown solid.Dissolve the solid in 32.5 mL of pyridine to make 0.4 M of solution.Take 5 mL of the solution (2.0 mmol), mix with(S)-2-(4-methoxy-phenyl)-piperazine (440 mg, 2.0 mmol) and heat to 100°C. for 2.5 hours. Cool the reaction to RT, concentrate down to aresidue, which purify by flash chromatography on silica gel, gradient100% CH₂Cl₂ to 100% mixed solvent of (CH₂Cl₂: 2N NH₃/MeOH=20:1) over 55min. give 250 mg of the title compound. Mass spectrum (APCI) (m/e):C₂₅H₂₉N₅OS, Cacl. Mass: 447.21, Found: 448.2(M+1); ¹H NMR (300 MHz,CDCl₃) δ ppm: 7.12-6.80 (m, 7H), 6.68-6.65 (m, 1H), 5.30 (br, 1H), 4.25(m, 2H), 3.77 (s, 3H), 3.21-2.88 (m, 4H), 2.85-2.79 (m, 3H), 2.67-2.62(m, 2H), 1.77-1.75 (m, 2H), 1.29 (t, 3H, J=7.3 Hz).

Example 502(S)-2-Ethyl-10-{3-[2-(4-fluoro-phenyl)-ethyl}-piperazin-1-yl}-4H-3-thia-1,4,9-benzo[f]azulene

By using a method similar to the method of Example 501, using asuspension of 2-ethyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo{f}azulene-10-thione (3.4 g, 13.0 mmol) in 35 mL CH₂Cl₂, add methyltrifluoromethanesulfonate (4.2 g, 26.0 mmol) overnight, LC-MS showedstill had 50% of starting material, added another 0.1 mL of methyltrifluoromethanesulfonate, and heated to 35° C. for 1 h. Concentrate thereaction mixture under reduced pressure, give a red-brown solid.Dissolve the solid in 32.5 mL of pyridine to make 0.4 M of solution.Take 6.25 mL of the solution (2.5 mmol), mix with(S)-2-(4-fluoro-phenyl)-piperazine (520 mg, 2.5 mmol) and heat to 100°C. for 3 hours. Cool the reaction to RT, concentrate down to a residue,which purify by flash chromatography on silica gel, gradient 100% CH₂Cl₂to 100% mixed solvent of (CH₂Cl₂:2N NH₃/MeOH=20:1) over 55 min. give 360mg of the title compound as orange-brown foam. Mass spectrum (APCI)(m/e): C₂₄H₂₆FN₅S, Cacl. Mass: 435.15, Found: 436.2 (M+1); ¹H NMR (300MHz, CDCl₃) δ ppm: 7.17-6.86 (m, 7H), 6.66-6.63 (m, 1H), 5.30 (br, 1H),4.25-4.15 (m, 2H), 3.10-2.66 (m, 10H), 1.76-1.71 (m, 2H), 1.28 (t, 3H,J=7.7 Hz).

Example 503(S)-2-Ethyl-10-{3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulene

By using a method similar to the method of Example 501, using asuspension of2-ethyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo{f}azulene-10-thione (3.4g, 13.0 mmol) in 35 mL CH₂Cl₂, add methyl trifluoromethanesulfonate (4.2g, 26.0 mmol) overnight, LC-MS showed still had 50% of startingmaterial, added another 0.1 mL of methyl trifluoromethanesulfonate, andheated to 35° C. for 1 h. Concentrate the reaction mixture under reducedpressure, give a red-brown solid. Dissolve the solid in 32.5 mL ofpyridine to make 0.4 M of solution. Take 6.25 mL of the solution (2.5mmol), mix with (S)-2-(3-fluoro-phenyl)-piperazine (520 mg, 2.5 mmol)and heat to 100° C. for 3 hours. Cool the reaction to RT, concentratedown to a residue, which purify by flash chromatography on silica gel,gradient 100% CH2C12 to 100% mixed solvent of (CH₂CI₂: 2N NH₃/MeOH=20:1)over 55 min. give 412 mg of the title compound Mass spectrum (APCI)(m/e): C₂₄H₂₆FN₅S, Cacl. Mass: 435.15, Found: 436.2 (M+1); ¹H NMR (300MHz, CDCl₃) δ ppm: 7.24-6.85 (m, 7H), 6.66-6.65 (m, 1H), 5.30 (br, 1H),4.25-4.15 (m, 2H), 3.20-2.68 (m, 10H), 1.90-1.75 (m, 2H), 1.29 (t, 3H,J=7.3 Hz).

Example 504(S)-2-Ethyl-10-{3-[2-(3-methoxy-phenyl)-ethyl]-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulene

By using a method similar to the Example 501, using a suspension of2-ethyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo{f}azulene-10-thione (3.4g, 13.0 mmol) in 35 mL CH₂Cl₂, add methyl trifluoromethanesulfonate (4.2g, 26.0 mmol) overnight, LC-MS showed still had 50% of startingmaterial, added another 0.1 mL of methyl trifluoromethanesulfonate, andheated to 35° C. for 1 h. Concentrate the reaction mixture under reducedpressure, give a red-brown solid. Dissolve the solid in 32.5 mL ofpyridine to make 0.4 M of solution. Take 6.25 mL of the solution (2.5mmol), mix with (S)-2-(3-methoxy-phenyl)-piperazine (550 mg, 2.5 mmol)and heat to 100° C. for 3 hours. Cool the reaction to RT, concentratedown to a residue, which purify by flash chromatography on silica gel,gradient 100% CH2Cl₂ to 100% mixed solvent of (CH₂CI₂: 2N NH₃/MeOH=20:1)over 55 min. give 306 mg of the title compound. Mass spectrum (APCI)(m/e): C₂₅H₂₉N₅OS, Cacl. Mass: 447.21, Found: 448.2(M+1); ¹H NMR (300MHz, CDCl₃) δ ppm: 7.21-7.16 (m, 1H), 7.08-6.96 (m, 2H), 6.91-6.86 (m,1H), 6.80-6.71(m, 3H), 6.65-6.64 (m, 1H), 5.40 (br, 1H), 4.35-4.25 (m,2H), 3.78 (s, 3H), 3.16-2.69 (m, 10H), 1.79-1.76 (m, 2H), 1.29 (t, 3H,J=7.7 Hz).

Example 506(S)-2-Ethyl-10-{3-[2-(4-methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulene,dihydrochloride

By using a similar method to Example 492, using(S)-2-ethyl-10-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulene,(190 mg, 0.42 mmol), formaldehyde (37%, w/w, aq) (42.7 mg, 0.53 mmol)and sodium triacetoxyborohydride (134.9 mg, 0.64 mmol) in 5 mL1,2-dichloroethane and stir at RT. After purification, give 145 mg offree base as brown oil: mass spectrum (APCI) (m/e): C₂₆H₃₁N₅OS, Cacl.Mass: 461.22, Found: 462.2(M+1); The dihydrochloric salt is form byadding 5 eq of acetyl chloride (115 mg, 1.46 mmol) to the free base (135mg, 0.292 mmol) in ethanol (5 mL). After removing the solvent, theresidue dissolve in 10 ml mix solvent of CH₃CN/H₂O=50/50, lyophilizeovernight, afford 142 mg of title compound as orange solid.

Example 507(S)-2-Ethyl-10-{3-[2-(4-fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl]-4H-3-thia-1,4,9-triaza-benzo[f]azulenedihydrochloride

By using a method similar to Example 492, using(S)-2-ethyl-10-{3-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulene,(292 mg, 0.67 mmol), formaldehyde (37%, w/w, aq) (68 mg, 0.84 mmol) andsodium triacetoxyborohydride (213 mg, 1.01 mmol) in 6 mL1,2-dichloroethane and stir at RT. After purification, give 272 mg offree base as yellow solid. Mass spectrum (APCI) (m/e): C₂₅H₂₈FN₅S, Cacl.Mass: 449.15, Found: 450.2; The dihydrochloric salt is form by adding 5eq of acetyl chloride (115 mg, 1.46 mmol) to the free base (135 mg,0.292 mmol) in ethanol (5 mL). After removing the solvent, the residuedissolve in 10 ml mix solvent of CH₃CN/H₂O=50/50, lyophilize overnight,afford 300 mg of title compound as yellow solid.

Example 508(S)-2-Ethyl-10-{3-[2-(3-fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulenedihydrochloride

By using a method similar to Example 492, using(S)-2-ethyl-10-{3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulene,(236 mg, 0.54 mmol), formaldehyde (37%, w/w, aq) (55 mg, 0.68 mmol) andsodium triacetoxyborohydride (172 mg, 0.81 mmol) in 6 mL1,2-dichloroethane and stir at RT. After purification, give 140 mg offree base: mass spectrum (APCI) (m/e): C₂₅H₂₈FN₅S, Cacl. Mass: 449.20,Found: 450.2 (M+1); ¹H NMR (300 MHz, CDCl₃) δ ppm: 7.24-7.19 (m, 1H),7.07-6.84 (m, 6H), 6.64-6.61 (m, 1H), 5.29 (br, 1H), 4.35-4.25 (m, 2H),3.27-3.23 (m, 1H), 3.04-2.71 (m, 5H), 2.62-2.42 (m, 2H), 2.33-2.29 (m,4H), 2.00-1.74 (m, 2H), 1.29 (t, 3H, J=7.7 Hz). The dihydrochloric saltis form by adding 5 eq of acetyl chloride (122 mg, 1.56 mmol) to thefree base (140 mg, 0.31 mmol) in ethanol (5 mL). After removing thesolvent, the residue dissolve in 10 ml mix solvent of CH₃CN/H₂O=50/50,lyophilize overnight, afford 139 mg of title compound as orange solid.

Example 509(S)-2-Ethyl-10-{3-[2-(3-methoxy-2-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulenedihydrochloride

By using a method similar to the method of Example 492, using(S)-2-ethyl-10-{3-[2-(3-methoxy-phenyl)-ethyl]-piperazin-1-yl}-4H-3-thia-1,4,9-triaza-benzo[f]azulene,(252 mg, 0.56 mmol), formaldehyde (37%, w/w, aq) (57 mg, 0.70 mmol) andsodium triacetoxyborohydride (179.2 mg, 0.85 mmol) in 5 mL1,2-dichloroethane and stir at RT. After purification, give 215 mg offree base. Mass spectrum (APCI) (m/e): C₂₆H₃₁N₅OS, Cacl. Mass: 461.22,Found: 462.2(M+1); The dihydrochloric salt is form by adding 5 eq ofacetyl chloride (168.8 mg, 2.15 mmol) to the free base (200 mg, 0.43mmol) in ethanol (5 mL). After removing the solvent, the residuedissolve in 10 ml mix solvent of CH₃CN/H₂O=50/50, lyophilize overnight,afford 225 mg of title compound.

Example 510N-(2,4-Dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2,2,2-trifluoro-acetamide

Add 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (7.67 g,40.0 mmol), and 4-(dimethylamino)pyridine (0.244 g, 2.00 mmol) to asolution of 3-amino-1,5-dihydro-benzo[b][1,4]diazepine-2,4-dione (7.65g, 40.0 mmol) in anhydrous N,N-dimethylformamide (50 mL). Rinse solidsinto reaction with anhydrous N,N-dimethylformamide (50 mL), and coolreaction to 0° C. in an ice/water bath. Add via syringe trifluoroaceticacid (3.08 mL, 40.0 mmol). After 10 minutes, remove cooling, and after5.5 hours at ambient temperature, add an additional 0.2 equivalents of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.53 g) andtrifluoroacetic acid (0.62 mL) and stir at ambient temperature. After anovernight period, concentrate under reduced pressure to give a residue.Reconstitute the residue in isopropanol: chloroform (1:3, 20 mL) and set5 minutes. Collect solid formed by suction filtration, wash withisopropanol: chloroform (3:1), and dry at ambient temperature undervacuum to give the title compound. Filter the filtrate, which containedprecipitated solid and dry this solid at ambient temperature undervacuum to give a second crop of the title compound: mass spectrum (ESneg., m/e): 286.0 (M−1); ¹H NMR (300 MHz, DMSO-d₆): 10.93 (s, 2H), 9.42(d, 1H, J=6.9 Hz), 7.29-7.15 (m, 4H), 4.91 (d, 1H, J=7.2 Hz).

Example 5112-Trifluoromethyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione

CombineN-(2,4-dioxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-yl)-2,2,2-trifluoro-acetamide(3.02 g, 10.5 mmol) with Lawesson's Reagent,[2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide],(6.38 g, 15.8 mmol) in anhydrous toluene (60 mL), heat to reflux, andstir. After 16 hours, cool and stir for a few hours. Collect thereaction solid by suction filtration, wash with a small amount oftoluene, and dry at 40° C. for a few hours to give crude product (3.6g). Adsorb material on Silica gel 60 and purify by flash chromatography,eluting with a solution of 35% ethyl acetate in hexane. Combine andconcentrate the product-containing fractions under reduced pressure, anddry the product at 54° C. under vacuum for 4.5 hours to give the titlecompound: mass spectrum (APCI, m/e): 302 (M+1); ¹H NMR (300 MHz,DMSO-d₆): 11.39 (s, 1H), 9.57 (s, 1H), 7.03 (m, 3H), 6.77 (m, 1H).

Example 512(S)-10-13-{2-(3-Fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene

Following a method similar as described in Example 484, using2-trifluoromethyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione(4.025 g, 13.36 mmol) and methyl trifluoromethanesulfonate (2.27 mL,20.0 mmol), to formed the methylated intermediate. Take 1.38 g of thisintermediate (3.0 mmol), combine and then(S)-2-[2-(3-fluoro-phenyl)-ethyl]-piperazine (0.62 g, 3.0 mmol),followed by two chromatographic purifications, the first with apre-packed silica gel column, eluting with a gradient of a 3.5% solutionof 2M ammonia in methanol, in dichloromethane (0-100% indichloromethane); and the second with a pre-packed cation exchangecolumn, loading with methanol, and then eluting the product withincreasing concentrations of 2M ammonia in methanol, in dichloromethanegives the title compound (0.754 g): mass spectrum (APCI+, m/e): 476(M+1); ¹H NMR (300 MHz, DMSO-d₆), δ (ppm): 8.45 (s, 1H), 7.33-7.23 (m,1H), 7.05-6.80 (m, 6H), 6.74-6.68 (m, 1H), 4.06-3.80 (br. m, 2.94-2.76(m, 2H), 2.74-2.52 (m, 5H), 2.35 (br. s, 1H), 1.67-1.49 (m, 2H).

Example 513 (S)-10-{3-[2-(3-Fluoro-phenyl)-ethyl]-1-piperazin-1-y-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulenedihydrochloride

Add a solution of acetyl chloride (0.566 mL, 7.93 mmol) in absoluteethanol to a solution of(S)-10-{3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene(0.754 g, 1.59 mmol) in absolute ethanol and stir at ambienttemperature. Isolate the precipitated solid by suction filtration,washing with diethyl ether to give the title compound (0.660 g): massspectrum (APCI+, m/e): 476 (M+1−2HCl); exact mass spectrum (ES+, m/e,C₂₃H₂₁F₄N₅S.2HCl): calc. 476.1532 (M+1−2HCl), found 476.1530.

Example 514(S)-10-{3-[2-(4-Fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene

Using a method similar to in Example 484, using2-trifluoromethyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione(4.025 g, 13.36 mmol) and methyl trifluoromethanesulfonate (2.27 mL,20.0 mmol), to form the methylated intermediate. Take 1.38 g of thisintermediate (3.0 mmol), combine with(S)-2-[²-(4-fluoro-phenyl)-ethyl]-piperazine (0.62, 3.0 mmol), followedby chromatographic purification, eluting with a gradient of a 3.5%solution of 2M ammonia in ethanol, in dichloromethane (0-100% indichloromethane) gives the title compound (1.11 g): mass spectraum(APCI+, m/e): 476 (M+1); ¹H NMR (300 MHz, DMSO-d₆), δ (ppm): 8.67-8.36(m, 2H), 7.27-7.16 (m, 2H), 7.13-7.03 (m, 2H), 7.01-6.86 (m, 3H),6.75-6.68 (m, 1H), 4.24-3.96 (br. m, 2H), 3.39-2.91 (m, 5H), 2.75-2.51(m, 2H), 1.88-1.73 (m, 2H).

Example 515(S)-10-{3-[2-(4-Fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulenedihydrochloride

Using a method similar to Example 513, using(S)-10-{3-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene(0.27 g, 0.57 mmol) and a solution of acetyl chloride (0.203 mL, 2.84mmol) in absolute ethanol at ambient temperature gives the titlecompound (0.276 g): Exact mass spectrum (ES+, m/e, C₂₃H₂₁F₄N₅S.2HCl):calc. 476.1532 (M+1−2HCl), found 476.1532.

Example 516(S)-10-{3-[2-(3-Methoxy-phenyl)-ethyl]-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene

Using a method similar to Example 484, using2-trifluoromethyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione(4.025 g, 13.36 mmol) and methyl trifluoromethanesulfonate (2.27 mL,20.0 mmol), to form the methylated intermediate. Take 1.38 g of thisintermediate (3.0 mmol), combine with(S)2-[2-(3-Methoxy-phenyl)-ethyl]-piperazine (0.65 g, 3.0 mmol),followed by chromatographic purification, eluting with a gradient of a3.5% solution of 2M ammonia in methanol, in dichloromethane (0-100% indichloromethane) gives the title compound (0.99 g): mass spectrum(APCI+, m/e): 488 (M+1); ¹H NMR (300 MHz, DMSO-d₆), δ (ppm): 8.73-8.49(m, 2H), 7.21-7.15 (m, 1H), 6.99-6.88 (m, 3H), 6.79-6.69 (m, 4H),4.25-3.98 (br. m, 2H), 3.70 (s, 3H), 3.38-3.17 (m, 3H), 3.14-2.97 (m,2H), 2.74-2.52 (m, 2H), 1.90-1.80 (m, 2H).

Example 517(S)-10-{3-[2-(3-Methoxy-phenyl)-ethyl]-piperazin-1-yl]-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulenedihydrochloride

Using a similar method to the method of Example 513, using(S)-10-{3-[2-(3-methoxy-phenyl)-ethyl]-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene(0.29 g, 0.59 mmol) and a solution of acetyl chloride (0.212 mL, 2.97mmol) in absolute ethanol at ambient temperature gives the titlecompound (0.297 g): Exact mass spectrum (ES+, m/e, C₂₄H₂₄F₃N₅OS2HCl):calc. 488.1732 (M+1−2HCl), found 488.1724.

Example 518(S)-10-{3-[2-(4-Methoxy-phenyl)-ethyl]-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene

Using a method similar to Example 484, using2-trifluoromethyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione(4.025 g, 13.36 mmol) and methyl trifluoromethanesulfonate (2.27 mL,20.0 mmol), to form the methylated intermediate. Take 1.38 g of thisintermediate (3.0 mmol), combine with(S)-2-[2-(4-methoxy-phenyl)-ethyl]-piperazine (0.40 g, 1.8 mmol),followed by chromatographic purification, eluting with a gradient of a3.5% solution of 2M ammonia in methanol, in dichloromethane (0-100% indichloromethane) gives the title compound (0.625 g): mass spectrum(APCI+, m/e): 488 (M+1); ¹H NMR (300 MHz, DMSO-d₆), δ (ppm): 8.58 (s,1H), 7.13-7.03 (m, 2H), 6.99-6.86 (m, 3H), 6.85-6.78 (m, 2H), 6.75-6.69(m, 1H), 4.22-3.97 (br. m, 2H), 3.70 (s, 3H), 3.44-2.87 (m, 6H),2.68-2.46 (m, 2H), 1.84-1.71 (m, 2H).

Example 519(S)-10-{3-[2-(4-Methoxy-phenyl)-ethyl]-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulenedihydrochloride

Using a method similar to Example 513, using(S)-10-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene(0.252 g, 0.517 mmol) and a solution of acetyl chloride (0.184 mL, 2.58mmol) in absolute ethanol at ambient temperature gives the titlecompound (0.258 g): Exact mass spectrum (ES+, m/e, C₂₄H₂₄F₃N₅OS.2HCl):calc. 488.1732 (M+1−2HCl), found 488.1732.

Example 520(S)-10-{3-[2-(3-Methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene

Add sodium triacetoxyborohydride (0.23 g, 1.1 mmol) and aqueousformaldehyde (37% w/w, 0.083 mL, 1.1 mmol) to a solution of(S)-10-{3-[2-(3-methoxy-phenyl)-ethyl]-piperazin-1yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene (0.36 g,0.74 mmol) in methanol: dichloroethane (1:1) and stir. After 1.5 hours,concentrate the reaction under reduced pressure to remove methanol, andthen dilute with a saturated aqueous solution of sodium bicarbonate anddichloromethane, and separate the layers. Extract the aqueous layer withdichloromethane (2×), combine organics, and dry (sodium sulfate),filter, and concentrate under reduced pressure to a residue. Purify theresidue by flash chromatography, eluting with a gradient of a solutionof ethyl acetate: hexane (1:1) with 1% 2M ammonia in methanol added(40-100% in hexane over 30 minutes, then 100% for 10 minutes) to givethe title compound (0.223 g, 60%): mass spectrum (APCI+, m/e): 502(M+1); ¹H NMR (300 MHz, DMSO-d₆), δ (ppm): 8.48 (s, 1H), 7.19-7.10 (m,1H), 6.97-6.81 (m, 3H), 6.76-6.67 (m, 4H), 3.96-3.76 (br. m, 2H), 3.68(s, 3H), 3.15-3.02 (m, 1H), 2.93-2.81 (m, 1H), 2.80-2.69 (m, 1H),2.65-2.34 (m, 2H), 2.27-2.04 (m, 5H), 1.91-1.75 (m, 1H), 1.66-1.48 (m,1H).

Example 521(S)-10-{3-[2-(3-Methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl]-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulenedihydrochloride

Using a method similar to Example 513, using(S)-10-{3-[2-(3-methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene(0.223 g, 0.445 mmol) and a solution of acetyl chloride (0.157 mL, 2.22mmol) in absolute ethanol at ambient temperature gives the titlecompound. Exact mass spectrum (ES+, m/e, C₂₅H₂₆F₃N₅OS2HCl): calc.502.1888 (M+1−2HCl), found 502.1885.

Example 522(S)-10-{3-[2-(3-Fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene

Following the method similar to Example 520, using(S)-10-{3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene(0.37 g, 0.78 mmol), sodium triacetoxyborohydride (0.25 g, 1.2 mmol),and aqueous formaldehyde (0.0875 mL, 1.17 mmol) in methanol:dichloroethane gives the title compound (0.213 g): mass spectrum (APCI+,m/e): 490 (M+1); ¹H NMR (300 MHz, DMSO-d₆), δ (ppm): 8.47 (s, 1H),7.32-7.22 (m, 1H), 7.06-6.81 (m, 6H), 6.75-6.67 (m, 1H), 4.00-3.75 (m,2H), 3.17-3.03 (m, 1H), 2.93-2.81 (m, 1H), 2.80-2.70 (m, 1H), 2.69-2.40(m, 2H), 2.29-2.04 (m, 5H), 1.91-1.76 (m, 1H), 1.68-1.51 (m, 1H).

Example 523(S)-10-{3-[2-(3-Fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulenedihydrochloride

Using a method similar to Example 520, using(S)-10-{3-[2-(3-fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene(0.213 g, 0.435 mmol) and a solution of acetyl chloride (0.155 mL, 2.18mmol) in absolute ethanol at ambient temperature gives the titlecompound: mass spectrum (APCI+, m/e): 490 (M+1−2HCl); exact massspectrum (ES+, m/e, C₂₄H₂₃F₄N₅S.2HCl calc. 490.1689 (M+1−2HCl), found490.1686.

Example 524(S)-10-3-[2-(4-Methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene

Following a method similar to the method of Example 520, using(S)-10-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene(0.36 g, 0.74 mmol), sodium triacetoxyborohydride (0.23 g, 1.1 mmol),and aqueous formaldehyde (0.083 mL, 1.1 mmol) in methanol:dichloroethane gives the title compound (0.255 g): mass spectrum (APCI+,m/e): 502 (M+1); ¹H NMR (300 MHz, DMSO-d₆), δ (ppm): 8.48 (s, 1H),7.11-7.00 (m, 2H), 6.97-6.82 (m, 3H), 6.82-6.75 (m, 2H), 6.75-6.68 (m,1H), 3.96-3.78 (m, 2H), 3.69 (s, 3H), 3.15-3.02 (m, 1H), 2.91-2.67 (m,2H), 2.61-2.28 (m, 2H), 2.25-2.00 (m,. 5H),.1.88-1.72 (m, 1H), 1.61-1.44(m, 1H).

Example 525(S)-10-{3-[2-(4-Methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulenedihydrochloride

Using a method similar to the method of 513, using(S)-10-{3-[2-(4-methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene(0.255 g, 0.508 mmol) and a solution of acetyl chloride (181 mL, 2.54mmol) in absolute ethanol at ambient temperature gives the titlecompound (0.269 g): mass spectrum (APCI+, m/e): 502 (M+1−2HCl); exactmass spectrum (ES+, m/e, C₂₅H₂₆F₃N5OS.2HCl): calc. 502.1888 (M+1−2HCl),found 502.1881.

Example 526(S)-10-{3-[2-(4-Fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-trifluoromethyl-4H-3-1,4,9-triaza-benzo[f]azulene

Using a method similar to Example 486, using(S)-10-{3-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene(0.36 g, 0.76 mmol) gives partial conversion to the title compound afterovernight stirring at ambient temperature. Add another 1.3 equivalentsof aqueous formaldehyde (0.074 mL, 0.98 mmol), methanol, and deionizedwater. After 2.5 hours, concentrate the reaction under reduced pressureto remove methanol and water. Dilute the reaction with a saturatedaqueous solution of sodium bicarbonate, and dichloromethane, andseparate the layers. Extract the aqueous layer with dichloromethane(2X), combine the organics, and dry (sodium sulfate), filter, andconcentrate them under reduced pressure to a residue. Purify the residueby flash chromatography, eluting with a gradient of a solution of ethylacetate: hexane (1:1) with 1% 2M ammonia in methanol added (40-100% inhexane over 30 minutes, then 100% for 10 minutes) to give the titlecompound (0.392 g). Mass spectrum (APCI+, m/e): 490 (M+1); ¹H NMR (300MHz, DMSO-d₆), δ (ppm): 8.49 (s, 1H), 7.24-7.13 (m, 2H), 7.11-7.00 (m,2H), 6.97-6.81 (m, 3H), 6.75-6.68 (m, 1H), 3.96-3.75 (m, 2H), 3.16-3.03(m, 1H), 2.92-2.80 (m, 1H), 2.79-2.69 (m, 1H), 2.66-2.37 (m, 2H),2.28-2.01 (m, 5H), 1.89-1.73 (m, 1H), 1.65-1.47 (m, 1H).

Example 527(S)-10-13-[2-(4-Fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulenedihydrochloride

Using the method similar to Example 513, using(S)-10-{3-[2-(4-fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-trifluoromethyl-4H-3-thia-1,4,9-triaza-benzo[f]azulene(0.392 g, 0.801 mmol) and a solution of acetyl chloride (0.286 mL, 4.01mmol) in absolute ethanol at ambient temperature gives the titlecompound (0.269 g): mass spectrum (APCI+, m/e): 490 (M+1−2HCl); exactmass spectrum (ES+, m/e, C₂₄H₂₃F₄N₅S.2HCl): calc. 490.1689 (M+1−2HCl),found 490.1690.

Example 528 3-Bromo-2-nitro-benzo[b]thiophene

Add dropwise fuming nitric acid(90%, 8.6 mL, 183 mmol) to a mixture of3-bromo benzo[b]thiophene (39g, 183 mmol) in TFA(100 mL) anddichloromethane (400mL) at 0° C. The reaction turn greenish, then yellowprecipitates. To this reaction mixture, add dichloromethane (200 mL) andthe reaction stir at 0° C. for 30 min. Then pour the reaction intoice-water (2 L). Extract with dichloromethane (3×500mL) and the organiclayer dry over MgSO4. Evaporation give a yellow solid. The resultingyellow solid triturate with diethyl ether to give a yellow solid.(Total: 34.8 g, 73%). Mass spectrum (m/e): 259(M+1); ¹HNMR(300 MHz,DMSO-d₆) δ ppm: 7.70(tt, 2H), 8.04(d, 1H), 8.17(d, 1H). ³CNMR(75 MHz,DMSO-d₆) δ ppm: 112.5, 124.8, 126.9, 127.9, 131.3, 137.0, 137.2, 166.1.

Example 529 2-Nitro-Benzo[b]thiophene-3-carbonitrile

Combine 3-bromo-2-nitro-benzo[b]thiophene (33.0 g, 127.4 mmol), coppercyanide (17.1 g, 191.1 mmol) in DMF(150 mL), heat to 120 ° C. for threehours. The reaction cool to RT, pour on ice, then filter. The filtercake wash with dichloromethane. The organic layer separate and dry overMgSO₄, evaporation to give a DMF solution. Add water (400 mL) and theyellow solid precipitate out. After filtration, obtain a brownish solid(23.5 g, 90%). Mass spectrum (m/e): 205 (M+1); ¹HNMR (300 MHz, DMSO-d6)δ: 7.78(m, 2H), 8.04(d, 1H), 8.29(d, 1H). ¹³CNMR(75 MHz, DMSO-d6)δppm:105.9, 112.1, 125.0, 125.2, 128.8, 131.2, 135.9, 137.8, 158.0.

Example 530 2-Amino-benzo[b]thiophene-3-carbonitrile

Combine in a 500 mL schlenk flask,2-nitro-benzo[b]thiophene-3-carbonitrile (5.8 g, 28.4 mmol) and Pd/C(3.0 g, 10% w/w, 2.84 mmol) in 1,2-dichloroethane (120 ml), the reactionmixture is charged with a balloon of hydrogen. After overnight stirring,release the hydrogen, remove the catalyst by filtration, and wash thecatalyst by 1,2-dichloroethane several times. Concentrate down to aresidue, which purified by flash chromatography on silica gel, gradient(100% hexane to 100% of Hexane:CH₂Cl₂:EtOAc=50:50:2.5), afford brownishsolid 3.6 g of title compound (yield 73%). Mass spectrum: ES(+)(m/e):175(M+1); ¹H NMR (300MHz, DMSO-d6, ppm): δ 7.81 (br, 2H), 7.65-7.62 (m,1H), 7.28-7.24 (m, 2H), 7.11-7.01 (m, 1 H).

Example 5312-(5-Fluoro-2-nitro-phenylamino)-benzo[b]thiiophene-3-carbonitrile

Combine 2-amino-benzo[b]thiophene-3-carbonitrile (2.25 g, 12.5 mmol),2,4-difluoro-nitrobenzene (1.99 g, 12.5 mmol and Lithium hydroxide (0.58g, 25 mmol) ) in 30 mL of DMSO and heat to 50 ° C., after 4 hours, coolthe reaction to the RT, and pour on ice, stir for 30 min, extract withCH₂Cl₂, the combined solvent wash with water and brine, dry over Na₂SO₄.Concentrate down to a residue treat with MeOH, the orange precipitatecollect by suction filtration give title compound, 2.15 g. Concentratethe filtrate and purify by flash chromatography to give 0.22 g orangesolid. Total 2.35 g, yield 61%. Mass spectrum: ES(+) (m/e): 314((M+1):¹H NMR (300 MHz, DMSO-d6) δ: 10.35 (br, 1H), 8.31-8.25 (m, 1H),8.00-7.96 (m, 1H), 7.68-7.65 (m, 1H), 7.53-7.37 (m, 3 H), 7.13-7.07 9 m,1H); ¹³CNMR (75 MHz, DMSO-d6) δ ppm: 165.5 (d, J=254.5 Hz), 156.2, 139.8(d, J=12.5 Hz), 135.9, 134.8, 132.2, 129.3 (d, J=11.7 Hz),126.3, 125.2,123.0, 120.4, 113.5, 110.4 (d, J=24.0 Hz), 107.6 (d, J=27.4 Hz), 92.9.

Example 5329-Fluoro-11H-12-thia-6,11-diaza-dibenzo[a,f]azulen-5-ylamine,hydrochloride

Combine2-(5-fluoro-2-nitro-phenylamino)-benzo[b]thiiophene-3-carbonitrile (2.15g, 6.87 mmol) and Tin(II) chloride, dihydrate (4.65 g, 20.6 mmol) in amixed solvent of EtOH (25 mL) and 5.0 N HCl (25 mL), heat the suspensionto reflux for 3 hours, cool to RT. The title compound 1.73 g (yield 78%)is obtained as a yellow solid by suction filtration. Mass spectrum: ACPI(m/e): 284((M+1-HCl); ¹H NMR (300 MHz, DMSO-d6) δ 11.46 (br, 1H), 10.02(br, 1H), 9.02 (br, 2H), 7.90-7.87 (m, 1H), 7.71-7.68 (m, 1H), 7.46-7.40(m, 1H), 7.33-7.28 (m, 1H), 7.12-6.94 (m, 2H), 6.85-6.81(m, 1H).

Example 533(S)-9-Fluoro-5-[3-phenethyl-piperazine-1-yl]-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene

Combine 9-fluoro-11H-12-thia-6,11-diaza-dibenzo[a,f]azulen-5-ylaminehydrogen chloride (287 mg, 0.9 mmol), (S)-2-phenethyl-piperazine (340mg, 1.80 mmol) and diisopropylethyl amine (116 mg, 0.9 mmol) in DMSO(0.5 mL) and toluene (2.0 mL), stir and microwave (300 W, 125 ° C.) for8 h, then heat to 115 ° C. for 22 h. Cool the reaction to RT, dilutewith CH₂Cl₂, wash with H₂O and brine. Dry the organic layer with byNa₂SO₄. The crude material purify by chromatography on silica gel,gradient (100% CH₂Cl₂ to 100% CH₂Cl₂:2N NH₃/MeOH=25:1), give 137 mg oftitle compound.

Example 534(S)-9-Fluoro-5-[3-phenethyl-4-methyl-piperazine-1-yl]-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene,dihydrochloride

By using a method similar to the method of Example 492, using(S)-9-fluoro-5-[3-phenethyl-piperazine-1-yl]-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene,(92 mg, 0.2 mmol), formaldehyde (37%, w/w, aq) (20 mg, 0.25 mmol) andsodium triacetoxyborohydride (64 mg, 0.30 mmol) in 3 mL1,2-dichloroethane and stir at RT. After purification, give 82 mg offree base. Mass spectrum: ACPI (m/e): 471.10 ((M+1-HCl) Thedihydrochloric salt is form by adding 5 eq of acetyl chloride (68.4 mg,0.89 mmol) to the free base (82 mg, 0.17 mmol) in ethanol (5 mL). Afterremoving the solvent, the residue dissolve in 10 ml mix solvent ofCH₃CN/H₂O=50/50, lyophilize overnight, afford 81 mg of title compound asyellow solid.

Example 535(S)-9-Fluoro-5-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene

Add 9-fluoro-11H-12-thia-6,11-diaza-dibenzo[a,f]azulen-5-ylaminehydrochloride (0.66 g, 2.1 mmol) to a solution of(S)-2-[2-(4-methoxy-phenyl)-ethyl]-piperazine (0.91 g, 4.1 mmol) indimethyl sulfoxide: toluene (1:8, 9 mL). Add diisopropylethylamine (0.36mL, 2.1 mmol), heat to 110° C., and stir. After 51 hours, cool toambient temperature, and dilute with ethyl acetate and 0.1 N NaOH.Separate the aqueous layer and extract it with ethyl acetate (2×). Washall organics with a saturated solution of sodium chloride, and then dry(sodium sulfate), filter, and concentrate them under reduced pressure toan oil (1.27 g). Purify the oil by flash chromatography, eluting with agradient of a 3% solution of 2M ammonia in methanol, in dichloromethane(0-100% in dichloromethane). Reconstitute the material in ethyl acetateand wash it with a saturated solution of sodium chloride (2×) to removeresidual dimethylsulfoxide. Back extract the combined aqueous layerswith ethyl acetate. Dry (sodium sulfate) the organic phases, filter, andconcentrate them under reduced pressure to give the title compound(0.389 g): mass spectrum (APCI+, m/e): 487 (M+1).

Example 536(S)-9-Fluoro-5-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-11H-12-thia-6,11-diaza-benzo[a,f]azulenedihydrochloride

Using a method similar to the method Example 513, using(S)-9-fluoro-5-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene(0.070 g, 0.14 mmol) and a solution of acetyl chloride (0.052 mL, 0.72mmol) in absolute ethanol at ambient temperature gives the titlecompound (0.76 g): mass spectrum (APCI+, m/e): 487 (M+1-2HCl); exactmass spectrum (ES+, m/e, C₂₈H₂₇FN₄OS.2HCl): calc. 487.1968 (M+1-2HCl),found 487.1972.

Example 537(S)-9-Fluoro-5-{3-[2-(3-methoxy-phenyl)-ethyl]-piperazin-1-yl}-11H-12-thia-6,11-diaza-benzo[a,f]azulene

Using a method similar to the method of Example 535, using9-fluoro-11H-12-thia-6, 11-diaza-dibenzo[a,f]azulen-5-ylaminehydrochloride (0.62 g, 1.9 mmol) and(S)-2-[2-(3-methoxy-phenyl)-ethyl]-piperazine (0.85 g, 3.9 mmol), andpurifying by flash chromatography, eluting with a solution of 2% 2Mammonia in methanol, in dichloromethane (33-66% in dichloromethane over7 minutes, 66-100% over 28 minutes, 100% for 23 minutes) gives the titlecompound (0.251 g): mass spectrum (APCI+, m/e): 487 (M+1).

Example 538(S)-9-Fluoro-5-{3-[2-(3-methoxy-phenyl)-ethyl]-piperazin-1-yl}-11H-12-thia-6,11-diaza-benzo[a,f]azulenedihydrochloride

Using a method similar to the method of 513, using(S)-9-fluoro-5-{3-[2-(3-methoxy-phenyl)-ethyl]-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene(0.070 g, 0.14 mmol) and a solution of acetyl chloride (0.0514 mL, 0.720mmol) in absolute ethanol at ambient temperature gives the titlecompound (0.081 g). Exact mass spectrum (ES+, m/e, C₂₈H₂₇FN₄OS.2HCl):calc. 487.1968 (M+1-2HCl), found 487.1973.

Example 539(S)-9-Fluoro-5-{3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-11H-12-thia-6,11-diaza-benzo[a,f]azulene

Using a method similar to the method of Example 535, using9-fluoro-11H-12-thia-6,11-diaza-dibenzo[a,f]azulen-5-ylaminehydrochloride (0.66 g, 2.1 mmol) and(S)-2-[2-(3-fluoro-phenyl)-ethyl]-piperazine (0.86 g, 4.1 mmol),stirring at 110 ° C. for 24 hours, and purifying by flashchromatography, eluting with a solution of 3% 2M ammonia in methanol, indichloromethane (33-66% in dichloromethane over 15 minutes, 66-100% over30 minutes, 100% for 13 minutes) gives the title compound (0.307 g).Mass spectrum (APCI+, m/e): 475 (M+1).

Example 540(S)-9-Fluoro-5-{3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-11H-12-thia-6,11-diaza-benzo[a,f]azulenedihydrochloride

Using a method similar to the method 513, using(S)-9-Fluoro-5-{3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene(0.055 g, 0.12 mmol) and a solution of acetyl chloride (0.041 mL, 0.58mmol) in absolute ethanol at ambient temperature gives the titlecompound (0.062 g). Mass spectrum (APCI+, m/e): 475 (M+1-2HCl); exactmass spectrum (ES+, m/e, C₂₇H₂₄F₂N₄.S2HCl): calc. 475.1768 (M+1-2HCl),found 475.1781.

Example 541(S)-9-Fluoro-5-{3-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-11H-12-thia-6,11-diaza-benzo[a,f]azulene

Using a method similar to the method of Example 535, using9-fluoro-11H-12-thia-6,11-diaza-dibenzo[a,f]azulen-5-ylaminehydrochloride (0.66 g, 2.1 mmol) and(S)-2-[2-(4-fluoro-phenyl)-ethyl]-piperazine (0.86 g, 4.1 mmol), andstirring at 110 ° C. for 47.5 hours gives the title compound (0.426 g).Mass spectrum (APCI+, m/e): 475 (M+1).

Example 542(S)-9-Fluoro-5-{3-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-11H-12-thia-6,11-diaza-benzo[a,f]azulenedihydrochloride

Using a method similar to the method 513, using(S)-9-fluoro-5-{3-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene(0.062 g, 0.13 mmol) and a solution of acetyl chloride (0.047 mL, 0.66mmol) in absolute ethanol at ambient temperature gives the titlecompound (0.072 g). Mass spectrum (APCI+, m/e): 475 (M+1-2HCl); exactmass spectrum (ES+, m/e, C₂₇H₂₄F₂N₄S.2HCl): calc. 475.1768 (M+1-2HCl),found 475.1787.

Example 543

(S)-9-Fluoro-5-{3-[2-(4-methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene

Add sodium triacetoxyborohydride (0. 183 g, 0.863 mmol) and aqueousformaldehyde (37% w/w, 0.065 mL, 0.86 mmol) to a solutionof(S)-9-fluoro-5-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene(0.28 g, 0.58 mmol) in dichloroethane and stir. After 2 hours, dilutewith a saturated aqueous solution of sodium bicarbonate anddichloromethane, and separate the layers. Extract the aqueous layer withdichloromethane. (2×), combine organics, and wash them with a saturatedsolution of sodium chloride. Dry (sodium sulfate) the organics, filter,and concentrate them under reduced pressure to a residue (0.38 g).Purify the residue by flash chromatography, eluting with a gradient of asolution of ethyl acetate: hexane (3:2) with 1% 2M ammonia in methanoladded (in hexane) to give the title compound: (0.214 g, 74%). Massspectrum (APCI+, m/e): 501 (M+1).

Example 544(S)-9-Fluoro-5-{3-[2-(4-methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulenedihydrochloride

Add a solution of acetyl chloride (0.144 mL, 2.02 mmol) in absoluteethanol to a solution of(S)-9-fluoro-5-{3-[2-(4-methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene(0.174 g, 0.348 mmol) in absolute ethanol and stir briefly at ambienttemperature. Concentrate solution under reduced pressure to give anorange solid. Reconstitute the solid in acetonitrile: water (1:1),freeze-dry the solution in a dry-ice/acetone bath, and lyophilizeovernight to give the title compound (0.208 g) as a yellow solid: massspectrum (APCI+, m/e): 501 (M+1-2HCl); exact mass spectrum (ES+, m/e,C₂₉H₂₉FN₄OS.2HCl): calc. 501.2124 (M+1-2HCl), found 501.2130.

Example 545(S)-9-Fluoro-5-{3-[2-(3-methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene

Using a method similar to the method of Example 543, using(S)-9-fluoro-5-{3-[2-(3-methoxy-phenyl)-ethyl]-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene(0.164 g, 0.337 mmol), sodium triacetoxyborohydride (0.107 g, 0.505mmol), and aqueous formaldehyde (0.038 mL, 0.50 mmol) in dichloroethanegives the title compound (0.136 g): mass spectrum (APCI+, m/e): 501(M+1).

Example 546(S)-9-Fluoro-5-{3-[2-(3-methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-11H-11-thia-6,11-diaza-dibenzo[a,f]azulenedihydrochloride

Using a method similar to the method of Example 544, using(S)-9-fluoro-5-{3-[2-(3-methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene(0.110 g, 0.220 mmol) and a solution of acetyl chloride (0.0784 mL, 1.10mmol) in absolute ethanol at ambient temperature gives the titlecompound (0.123 g). Mass spectrum (APCI+, m/e): 501 (M+1-2HCl); exactmass spectrum (ES+, m/e, C₂₉H₂₉FN₄OS.2HCl): calc. 501.2124 (M+1-2HCl),found 501.2136.

Example 547(S)-9-Fluoro-5-{3-]2-(3-fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene

Using a method similar to Example 543, using(S)-9-fluoro-5-{3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-1H-12-thia-6,11-diaza-dibenzo[a,f]azulene(0.218 g, 0.459 mmol), sodium triacetoxyborohydride (0.146 g, 0.689mmol), and aqueous formaldehyde (0.052 mL, 0.69 mmol) in dichloroethanegives the title compound (0.185 g). Mass spectrum (APCI+, m/e): 489(M+1).

Example 548(S)-9-Fluoro-5-{3-[2-(3-fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulenedihydrochloride

Using a method similar to the method of Example 544, using(S)-9-fluoro-5-{3-[2-(3-fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene(0.144 g, 0.294 mmol) and a solution of acetyl chloride (0.105 mL, 1.47mmol) in absolute ethanol at ambient temperature gives the titlecompound (0.179 g). Mass spectrum (APCI+, m/e): 489 (M+1-2HCl); exactmass spectrum (ES+, m/e, C₂₈H₂₆F₂N₄S.2HCl): calc. 489.1924 (M+1-2HCl),found 489.1918.

Example 549(S)-9-Fluoro-5-{3-[2-(4-fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene

Using a method similar to the method of Example 543, using(S)-9-fluoro-5-{3-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene(0.339 g, 0.714 mmol), sodium triacetoxyborohydride (0.227 g, 1.07mmol), and aqueous formaldehyde (0.080 mL, 1.1 mmol) in dichloroethane,and employing a second chromatographic purification, eluting with agradient of a solution of ethyl acetate: hexane (1:1) with 2% 2M ammoniain methanol (in hexane) added, gives the title compound (0.238 g). Massspectrum (APCI+, m/e): 489 (M+1).

Example 550(S)-9-Fluoro-5-{3-[2-(4-fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulenedihydrochloride

Using a method similar to the method of Example 544, using(S)-9-fluoro-5-{3-[2-(4-fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-11H-12-thia-6,11-diaza-dibenzo[a,f]azulene(0.206 g, 0.422 mmol) and a solution of acetyl chloride (0.151 mL, 2.12mmol) in absolute ethanol at ambient temperature gives the titlecompound (0.228 g): mass spectrum (APCI+, m/e): 489 (M+1-2HCl); exactmass spectrum (ES+, m/e, C₂₈H₂₆F₂N₄S.2HCl): calc. 489.1924 (M+1-2HCl),found 489.1918.

Example 551 2-(2-nitro-phenylamino)-benzo[b]thiophene-3-carbonitrile

By using a method similar to the method of Example 490, combine2-amino-benzo[b]thiophene-3-carbonitrile (3.56 g, 20.5 mmol),2-fluoro-nitrobenzene (2.88 g, 20.5 mmol) and Lithium hydroxide (0.96 g,41.0 mmol) ) in 50 mL of DMSO and heat to 50 ° C., after over nightheating to give 5.0 g, yield 83%. Mass spectrum: ES(+) (m/e): 296.0((M+1); ¹H NMR (400 MHz, DMSO-d6) ppm: 10.27 (s, 1H), 8.13 (dd, 1H,J=1.7 Hz, J=8.3 Hz), 7.91-7.89 (m, 1H), 7.76-7.72 (m, 1H), 7.64-7.57 (m,2 H), 7.48-7.44 (m, 1H), 7.36-7.32 (m, 2H).

Example 552 11H-12-thia-6,11-diaza-dibenzo[a,f]azulen-5-ylaminehydrochloride

By using a method similar to the method of Example 532, combine2-(2-nitro-phenylamino)-benzo[b]thiophene-3-carbonitrile (5.0 g, 17.0mmol) and Tin(II) chloride (9.65 g, 51.0 mmol) in a mixed solvent ofEtOH (50 mL) and 5.0 N HCl (50 mL), heat the suspension to reflux for 3hours, cool to RT. The title compound 4.65 g (yield 91%) is obtained asa yellow solid by suction filtration. Mass spectrum: ACPI (m/e): 266.0((M+1-HCl); ¹H NMR (300 MHz, DMSO-d6) ppm: 11.7 (br, 1H), 10.00 (br,1H), 9.10 (br, 2H), 7.90-7.85 (m, 1H), 7.72-7.65 (m, 1H), 7.48-7.38 (m,1H), 7.35-7.28 (m, 1H), 7.22-6.98 (m, 4H).

Example 553 2-(2-Nitro-phenylamino)-benzonitrile

Combine 1-fluoro-2-nitro-benzene (5.00 g, 35.44 mmol),2-amino-benzonitrile (4.19 g, 35.44 mmol), lithium hydroxide monohydrate(2.97 g, 70.87 mmol) and DMSO (50.0 ml). Stir the mixture at 55 ° C. for19 hours then cool to ambient temperature. Pour the mixture onto icechips and stir for 1 hour. Remove the resulting precipitate by vacuumfiltration. Dry the precipitate under vacuum to give 6.14 g (72%) of anorange solid: mp 134-138°.

Example 554 5H-Dibenzo[b,e][1.4]diazepin-11-ylamine hydrochloride

Combine 2-(2-Nitro-phenylamino)-benzonitrile (6.14 g, 25.66 mmol),tin(II) chloride dihydrate (17.37 g, 76.99 mmol),5N HCl (105 ml), andethanol (65.0 ml). Stir the mixture at reflux for 24 hours then cool itto ambient temperature and chill it in the refrigerator for 2 hours.Remove the ethanol under vacuum and chill in the refrigerator again.Filter off the resulting precipitate by vacuum filtration and dry it ina vacuum oven to give 6.31 g (100%) of a yellow solid: mass spectrum(ion spray): m/z =210.0 (M+1).

Example 555 2-Amino-5-isopropyl-benzonitrile

Combine 2-bromo-4-isopropyl aniline (7.5 g, 35 mmol) and copper (I)cyanide (3.76 g, 42 mmol) in NMP (30.0 mL) and heat at 200° C. for 2hours. Cool to ambient temperature and dilute with water (300 mL).Extract with ethyl acetate to give 4.58 g of the crude product. Silicagel chromatography, eluting with methylene chloride, gives 3.20 g of thetitle compound as a red oil: mass spectrum (ion spray): m/z =161 (M+1);¹H NMR (300 MHz, DMSO-d₆): δ 7.21 (m, 2H), 6.73 (d, 1H), 5.79 (s, 2H),2.73 (quintet, 1H), 1.12 (d, 6H).

Example 556 5-Isopropyl-2-(2-nitro-phenylamino)-benzonitrile

Combine 2-amino-5-isopropyl-benzonitrile (3.19 g, 20 mmol),1-fluoro-2-nitro benzene (2.1 mL, 20 mmol) and lithium hydroxide (1.68g, 40 mmol) in DMSO (40.0 mL) and heat at 55° C. for 19 hours. Cool toambient temperature and dilute with water (200 mL). The title compoundprecipitates as 4.56 g of an orange solid: mp 91-96° C.; mass spectrum(ion spray) m/z =280 (M+1).

Example 557 2-Isopropyl-5H-dibenzo[b,e][1,4diazepin-11-ylaminehydrochloride

Combine 5-isopropyl-2-(2-nitro-phenylamino)-benzonitrile (4.54 g, 16.1mmol) and tin (II) chloride (10.92 g, 48.4 mmol) in 65.0 mL of SN HClsolution and 65.0 mL of ethanol. Heat this mixture at 86° C. for 18hours. Chilling the mixture precipitates the title compound as 4.22 g ofa yellow solid: mp>250° C.; mass spectrum (ion spray): m/z=252 (M+1).

Example 558 2-Amino-5-isopropyl-benzonitrile

Heat a mixture of copper (I) cyanide (2.5 g, 28.02 mmol), and2-bromo4-isopropyl-phenylamine (5.0 g, 23.35 mmol) in1-methyl-2-pyrrolidinone (20 ml) to 195° C. for four hours. Dilute thereaction mixture with 100 ml of ethyl acetate and wash the dark solutiontwice with 28% aqueous ammonium hydroxide, twice with saturated aqueoussodium chloride (brine) and twice with water. Collect the organic layer,dry over sodium sulfate and remove the solvent under reduced pressure.Purify the residue via flash chromatography eluting with a step gradientstarting with hexanes and going to 80% hexanes with 20% ethyl acetate toobtain 3.31 g (20.66 mmol, 88% yield) of the title compound as an orangeoil: Mass Spectrum (m/e): 161(M+1).

Example 559 2-(4-Fluoro-2-nitro-phenylamino)-5-isopropyl-benzonitrile

Heat a solution of 2-amino-5-isopropyl-benzonitrile (1.482 g, 9.25 mmol)with 1,4-difluoro-2-nitro-benzene (1.47 g, 9.25 mmol) and lithiumhydroxide monohydrate (0.78 g, 18.50 mmol) in DMSO (20 ml) to 70° C. for38 hours. Cool the reaction to ambient temperature and then pour intoapproximately 200 ml of ice water and stir for one hour. The titlecompound precipitates and collection by filtration to obtain 2.236 g(7.47 mmol, 81% yield) of the title compound as an orange amorphoussolid: Mass Spectrum (m/e): 300(M+1).

Example 560 8-Fluoro-2-isopropyl-5H-dibenzo[b,e][1,4]diazepin-11-ylaminehydrochloride

By using a method similar to the method of Example 532, using2-(4-fluoro-2-nitro-phenylamino)-5-isopropyl-benzonitrile (0.559 g,(1.87 mmol), tin (II) chloride(1.06 g, 5.60 mmol) to obtain (0.422 g,1.38 mmol, 74% yield) of the title compound as a yellow amorphous solid:Mass Spectrum (m/e): 270(M+1).

Example 561 2-(4-Fluoro-2-nitro-phenylamino)-5-methyl-benzonitrile

Combine 4-fluoro-2-nitro-phenylamine (2.9 g, 18.50 mmol),2-fluoro-5-methyl-benzonitrile (2.5 g, 18.50 mmol) and lithium hydroxidemonohydrate (2.4 g, 57.20 mmol) in methyl sulfoxide (DMSO, 40 ml). Heatthe resulting mixture to 55° C. for 40 hours. Cool the reaction mixtureto ambient temperature, then pour into approximately 250 ml of ice waterand stir for one hour. Filter the resulting mixture and collect theprecipitate. Chromatograph the solid using flash chromatography andelute with mobile phase: 90% hexanes, 5% ethyl acetate, and 5%dichloromethane. Obtained 2.267 g of the title compound (8.36 mmol, 45%yield) as an orange amorphous solid.

Mass Spectrum (m/e): 272(M+1).

Example 562 8-Fluoro-2-methyl-5H-dibenzo[b,e][1,4diazepin-11-ylaminehydrochloride

Heat a solution of2-(⁴-fluoro-2-nitro-phenylamino)-5-methyl-benzonitrile (1.747 g, 6.44mmol) in ethanol (35 ml) to 60° C. and add a solution of tin (II)chloride (6.06 g, 31.96 mmol) in 5.0 N hydrochloric acid (35 ml). Refluxthe resulting mixture to reflux for 40 hours. Cool the reaction to roomtemperature and place in a freezer for 16 hours. The productprecipitates from the solution and is collected by filtration to obtain1.3 g of the title compound (4.68 mmol, 73% yield) as a yellow-greenamorphous solid: Mass Spectrum (m/e): 241 (M+1).

Example 563 4-methyl-2-(2-nitro-phenylamino)-benzonitrile

Combine 1-fluoro-2-nitro-benzene (5.34 g, 37.83 mmol),2-amino-4-methyl-benzonitrile (5.00 g, 37.83 mmol), lithium hydroxidemonohydrate (3.17 g, 75.66 mmol) and DMSO (70.0 ml). Stir the mixture at55° C. for 16 hours then cool it to ambient temperature. Pour themixture onto ice chips and stir for 1 hour. Remove the resulting yellowprecipitate by vacuum filtration. Dry the precipitate under vacuum thenrecrystallize it in ethanol to give 5.15 g (54%) of fine, amber coloredneedles: mp 162-164°; mass spectrum (ion spray): m/z =254.0 (M+1).

Example 564 5-methyl-2-(2-nitro-phenylamino)-benzonitrile

Combine 1-fluoro-2-nitro-benzene (4.34 g, 30.79 mmol),2-amino-5-methyl-benzonitrile (4.07 g, 30.79 mmol), lithium hydroxidemonohydrate (2.58 g, 61.58 mmol) and DMSO (50.0 ml). Stir the mixture at55° C. for 22 hours then cool it to ambient temperature. Pour themixture onto ice chips and stir for 1 hour. Remove the resultingprecipitate by vacuum filtration. Dry the precipitate under vacuum thenpurify it on silica gel using dichloromethane/hexanes (75:25) to give4.45 g (57%) of an orange solid: mp 135-139°; mass spectrum (ion spray):m/z=254.0 (M+1).

Example 565 2-Amino-5-methyl-benzonitrile

Combine 2-bromo-4-methyl-phenylamine (8.00 g, 43.0 mmol), CuCN (4.62 g,51.6 mmol), and NMP (30.0 ml). Stir the mixture at reflux for 75 minutesthen cool it to ambient temperature. Pour the mixture onto ice chips andstir for 1 hour. Remove the resulting precipitate by vacuum filtration.Dissolve the precipitate in NH₄OH and extract it with dichloromethane.Combine, wash (brine), dry (sodium sulfate), and reduce the extracts toresidue. Purify the residue on silica gel using dichloromethane/hexanes(75:25) to give 3.39 g (60%) of an orange solid: mass spectrum (ionspray): m/z=133.1 (M+1).

Example 566 2-Methyl-5H-dibenzo[b,e][1,4]diazepin-11-ylaminehydrochloride

Combine 5-methyl-2-(2-nitro-phenylamino)-benzonitrile (4.03 g, 15.91mmol), tin(II) chloride dihydrate (10.77 g, 47.74 mmol), 5N HCl (65 ml),and ethanol (40.0 ml). Stir the mixture at reflux for 7 hours then coolit to ambient temperature and chill it in the refrigerator overnight.Remove the resulting precipitate by vacuum filtration. Place theprecipitate in ethanol (100.0 ml) and 5N HCl (20.0 ml) and heat atreflux for 19 hours. Cool the reaction mixture to ambient temperaturethen chill it in the refrigerator. Filter off the resulting precipitateby vacuum filtration and dry it in a vacuum oven to give 2.59 g (63%) ofan orange solid: mass spectrum (ion spray): m/z=224.0 (M+1).

Example 567 3-Methyl-5H-dibenzo[b,e][1,4]diazepin-11-ylaminehydrochloride

Combine 4-methyl-2-(2-nitro-phenylamino)-benzonitrile (2.46 g, 9.71mmol), tin(II) chloride dihydrate (6.57 g, 29.71 mmol), 5N. HCl (40 ml),and ethanol (40.0 ml). Stir the mixture at reflux for 8 hours then coolit to ambient temperature. Allow the mixture to stand at ambienttemperature overnight then chill it for 3 hours in the refrigerator.Remove the resulting precipitate by vacuum filtration and dry it undervacuum to give 1.24 g (49%) of the desired compound as a yellow solid:mass spectrum (ion spray): m/z=224.0 (M+1).

Example 568(S)-8-Fluoro-11-{3-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-methyl-5H-dibenzo[b,e][1,4]diazepinesuccinate

Heat a solution of8-fluoro-2-methyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride(0.391 g, 1.62 mmol) and (S)-2-[2-(4-fluoro-phenyl)-ethyl]-piperazine(0.68 g, 3.24 mmol) in 1-methyl-2-pyrrolidinone (8mL) to 195° C. for 14hours. Cool reaction mixture to ambient temperature. Dilute with 100 mlof ethyl acetate and wash twice with brine, twice with water, and onceagain with brine. Collect the organic layer and dry over sodium sulfate.Remove solvent under reduced pressure. Purification via flashchromatography, eluting with a step gradient starting with 100% of astock mixture of 75% ethyl acetate with 25% dichloromethane and going to90% of the stock mixture with 10% 2M ammonia in methanol, gives the freebase of the title compound (0.108 g, 0.25 mmol, 15% yield) as a yellowamorphous solid. Convert the product to the succinate salt by dissolvingthe product in methanol and adding one equivalent of succinic acid,swirl or sonicate the mixture until no solid succinic acid remains, thenremoving the solvent under reduced pressure gives the title compound:Mass Spectrum (m/e): 433(M+1).

Example 569(S)-8-Fluoro-11-{3-[2-(4-fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-methyl-5H-dibenzo[b,e][1,41diazepinesuccinate

Dissolve(S)-8-fluoro-11-{3-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-methyl-5H-dibenzo[b,e][1,4]diazepine(0.076 g, 0.18 mmol) in dichloromethane (10 ml). Add sodiumtriacetoxyborohydride (0.112 g, 0.53 mmol) and formaldehyde (0.011 g,0.35 mmol, 0.029 g of a 37% aqueous solution) and stir the mixture forone hour at ambient temperature. Dilute the mixture with brine andextract three times with dichloromethane. Combine the organic layers,dry over sodium sulfate and remove the solvent under reduced pressure.Purification via flash chromatography, eluting with a step gradientstarting with 100% of a stock mixture of 70% hexanes with 30%dichloromethane and going to 90% of the stock mixture with 10% 2Mammonia in methanol, gives the free base of the title compound (0.028 g,0.06 mmol, 36% yield) as a yellow foam. Convert to to the succinate saltas described previously: Mass Spectrum (m/e): 446(M+1).

Example 570(S)-8-Fluoro-11-{3-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-isopropyl-5H-dibenzo[b,e][1,4]diazepinesuccinate

Heat a solution of8-fluoro-2-isopropyl-5H-dibenzo[b,e][1,4]diazepin-11-ylaminehydrochloride (0.308 g, 1.01 mmol) and(S)-2-[2-(4-fluoro-phenyl)-ethyl]-piperazine (0.629 g, 3.02 mmol) in1-methyl-2-pyrrolidinone (8 mL) to 195° C. for 14 hours. Cool reactionmixture to ambient temperature. Dilute with 50 ml of ethyl acetate andwash twice with brine, twice with water, and once again with brine.Collect the organic layer and dry over sodium sulfate. Remove solventunder reduced pressure. Purification via flash chromatography, elutingwith a step gradient starting with 100% of a stock mixture of 80% ethylacetate with 20% dichloromethane and going to 95% of the stock mixturewith 5% 2M ammonia in methanol, gives the free base of the titlecompound (0.132 g, 0.29 mmol, 28% yield) as a yellow amorphous solid.Convert to the succinate salt as described previously: Mass Spectrum(m/e): 461(M+1).

Example 571(S)-8-Fluoro-11-{3-[2-(4-fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-isopropyl-5H-dibenzo[b,e][1,4]diazepinesuccinate

Dissolve(S)-8-fluoro-11-{3-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-isopropyl-5H-dibenzo[b,e][1,4]diazepine(0.066 g, 0.14 mmol) in dichloromethane (8 ml). Add sodiumtriacetoxyborohydride (0.091 g, 0.43 mmol) and formaldehyde (0.009 g,0.29 mmol, 0.023 g of a 37% aqueous solution) and stir the mixture forone hour at ambient temperature. Dilute the mixture with brine andextract three times with dichloromethane. Combine the organic layers,dry over sodium sulfate and remove the solvent under reduced pressure.Purification via flash chromatography, eluting with a step gradientstarting with 100% of a stock mixture of 70% hexanes with 30%dichloromethane and going to 90% of the stock mixture with 10% 2Mammonia in methanol, gives the free base of the title compound (0.032 g,0.07 mmol, 47% yield) as a yellow foam. Convert to the succinate salt asdescribed previously: Mass Spectrum (m/e): 475(M+1).

Example 572(S)-11-{3-[2-(3-Fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-isopropyl-5H-dibenzo[b,e][1,4]diazepine

Combine 2-isopropyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine (0.665 g,2.31 mmol) and (S)-2-[2-(3-fluoro-phenyl)-ethyl]-piperazine (0.962 g,4.62 mmol)in toluene (4.0 mL) and DMSO (1.0 mL) and heat at 110° C. for18 hours. Cool to ambient temperature and dilute with ethyl acetate (75mL). Wash with 0.1N NaOH solution, water and evaporate to give 0.996 gof the crude product. Silica gel chromatography, eluting with methylenechloride: 2N NH₃/methanol (100:4), gives 0.216 g of the title compoundas a tan solid: mass spectrum (ion spray): n/z=443 (M+1).

Example 573(S)-11-{3-[2-(3-Fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-isopropyl-5H-dibenzo[b,e][1,4diazepine dihydrochloride

In a manner such as that described in Example 461, using(S)-11-{3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-isopropyl-5H-dibenzo[b,e][1,4]diazepine(0.351 g, 0.79 mmol) gives 0.176 g of the title compound as an orangesolid: mp 227° C.; mass spectrum (ion spray): m/z =457 (M+1); Analysisfor C₂₉H₃₅Cl₂FN₄(0.2H₂O): calcd: C, 65.33; H, 6.69; N, 10.51; found: C,65.22; H, 6.70; N, 10.39.

Example 5743-Methyl-11-(4-methyl-piperazin-1-yl)-3-methyl-5H-dibenzo[b,e][1,4]diazepine

Combine 3-methyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride(636.4 mg, 2.85 mmol), N-methylpiperazine (444.2 mg, 3.08 mmol),N,N-diisopropylethylamine (856.5 mg, 8.55 mmol), DMSO (2.0 ml), andtoluene (4.0 ml). Stir and heat the mixture at 110° C. After 48 hours,add one drop of 5N HCl. After 72 hours, cool the mixture to ambienttemperature and then dilute it with ethyl acetate. Wash the organiclayer with DI H₂O and brine. Dry (sodium sulfate) and concentrate theorganic layer to residue. Purify the residue on silica gel usingdichloromethane/methanol (90:10) to give 362.9 mg (42%) of a tan foam:mp 84°, dec; mass spectrum (ion spray): m/z=307.1 (M+1).

Example 5753-Methyl-11-[(S)-3-phenethyl-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine

Combine 3-methyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride(400.0 mg, 1.54 mmol), (S)-2-phenethyl-piperazine (879.1 mg, 4.62 mmol),N,N-diisopropylethylamine (199.0 mg, 1.54 mmol), DMSO (0.7 ml), andtoluene (2.8 ml). Stir and heat the mixture at 110° C. After 65 hours,cool the mixture to ambient temperature and then dilute it with ethylacetate. Wash the organic layer with 0.1 N NaOH and brine. Dry (sodiumsulfate) and concentrate the organic layer to residue. Purify theresidue on silica gel using dichloromethane/methanol (90:10) to give518.7 mg (85%) of a tan foam: mp 64°-80°; mass spectrum (ion spray):m/z=397.2 (M+1).

Example 5763-Methyl-11-[4-methyl-(S)-3-phenethyl-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine

Combine3-methyl-11-[(S)-3-phenethyl-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine(375.0 mg, 0.95 mmol), formaldehyde (84.4 μL, 1.04 mmol, 37% in water),and 1,2-dichloroethane (30.0 ml). Stir the mixture at ambienttemperature for 5 minutes and then add sodium triacetoxyborohydride(300.6 mg, 1.42 mmol). After stirring for 30 minutes at ambienttemperature, quench the reaction with saturated sodium bicarbonate.Remove the organic portion and wash (brine), dry (sodium sulfate), andreduce the extracts to residue. Purify the residue on silica gel usingdichloromethane/methanol (90:10) to give 329.5 mg (85%) of the titlecompound as a tan foam: mp 65°, dec; mass spectrum (ion spray):m/z=411.3 (M+1).

Example 57711-{(S)-3-[2-(3-Fluoro-phenyl)-ethyl]-piperazin-1-yl}-3-methyl-5H-dibenzo[b,e][1,4]diazepine

Combine 3-methyl-5H-dibenzo[b,e][1,4]diazepin-1-ylamine hydrochloride(400.0 mg, 1.54 mmol), (S)-2-[2-(3-Fluoro-phenyl)-ethyl]-piperazine(641.5 mg, 3.08 mmol), N,N-diisopropylethylamine (199.0 mg, 1.54 mmol),DMSO (0.7 ml), and toluene (2.8 ml). Stir and heat the mixture at 110°C. After 64 hours, cool the mixture to ambient temperature and thendilute it with ethyl acetate. Wash the organic layer with 0.1 N NaOH andbrine. Dry (sodium sulfate) and concentrate the organic layer toresidue. Purify the residue on silica gel using dichloromethane/methanol(90:10) to give 423.2 mg (66%) of a tan foam: mp 81°, dec; mass spectrum(ion spray): m/z 415.2 (M+1).

Example 57811-{(S)-3-[2-(3-Fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-3-methyl-5H-dibenzo[b,e][1,4]diazepine

Combine11-{(S)-3-[2-(3-fluoro-phenyl)-ethyl]-piperazin-1-yl}-3-methyl-5H-dibenzo[b,e][1,4]diazepine(385.5 mg, 0.93 mmol), formaldehyde (83.0 μL, 1.02 mmol, 37% in water),and 1,2-dichloroethane (30.0 ml). Stir the mixture at ambienttemperature for 5 minutes and then add sodium triacetoxyborohydride(295.6 mg, 1.39 mmol). After stirring for 30 minutes at ambienttemperature, quench the reaction with saturated sodium bicarbonate.Remove the organic portion and wash (brine), dry (sodium sulfate), andreduce the extracts to residue. Purify the residue on silica gel usingdichloromethane/methanol (90:10) to give 366.2 mg (92%) of the titlecompound as a yellow foam: mp 63°, dec; mass spectrum (ion spray):m/z=429.3 (M+1).

Example 5792-Methyl-11-(4-methyl-piperazin-1-yl)-3-methyl-5H-dibenzo[b,e][1,4]diazepine

Combine 2-methyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride(600.0 mg, 2.31 mmol), N-methylpiperazine (1.39 g, 13.86 mmol),N,N-diisopropylethylamine (298.6 mg, 2.31 mmol), DMSO (1.0 ml), andtoluene (4.0 ml). Stir and heat the mixture at 110° C. After 48 hours,cool the mixture to ambient temperature and stir it overnight. Dilutethe mixture with ethyl acetate and wash the organic layer with 0.1N NaOHand brine. Dry (sodium sulfate) and concentrate the organic layer toresidue. Purify the residue on silica gel using dichloromethane/methanol(90:10) to give 550.5 mg (78%) of a tan foam: mp 170°-177°, dec; massspectrum (ion spray): m/z=307.2 (M+1).

Example 5802-Methyl-11-[(S)-3-phenethyl-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine

Combine 2-methyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride(600.0 mg, 2.31 mmol), (S)-2-phenethyl-piperazine (879.1 mg, 4.62 mmol),N,N-diisopropylethylamine (298.6 mg, 2.31 mmol), DMSO (1.0 ml), andtoluene (4.0 ml). Stir and heat the mixture at 110° C. After 67 hours,cool the mixture to ambient temperature and then dilute it with ethylacetate. Wash the organic layer with 0.1 N NaOH and brine. Dry (sodiumsulfate) and concentrate the organic layer to residue. Purify theresidue on silica gel using dichloromethane/methanol (90:10) to give646.3 mg (71%) of a tan foam: mp 67°, dec; mass spectrum (ion spray):m/z=397.3 (M+1).

Example 5812-Methyl-11-[4-methyl-(S)-3-phenethyl-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine

Combine2-methyl-11-[(S)-3-phenethyl-piperazin-1-yl]-5H-dibenzo[b,e][1,4]diazepine(300.0 mg, 0.76 mmol), formaldehyde (67.5 μL, 0.83 mmol, 37% in water),and 1,2-dichloroethane (25.0 ml). Stir the mixture at ambienttemperature for 5 minutes and then add sodium triacetoxyborohydride(240.5 mg, 1.13 mmol). After stirring for 30 minutes at ambienttemperature, quench the reaction with saturated sodium bicarbonate.Remove the organic portion and wash (brine), dry (sodium sulfate), andreduce the extracts to residue. Purify the residue on silica gel usingdichloromethane/methanol (90:10) to give 279.7 mg (90%) of the titlecompound as a yellow foam: mp 65°, dec; mass spectrum (ion spray):m/z=411.2 (M+1).

Example 582 11-(4-Methyl-piperazin-1-yl)-5H-dibenzo[b,e][1,4]diazepine

Combine 5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride (600.0 mg,2.44 mmol), N-methylpiperazine (1.47 g, 14.65 mmol),N,N-diisopropylethylamine (315.6 mg, 2.44 mmol), DMSO (1.0 ml), andtoluene (4.0 ml). Stir and beat the mixture at 110° C. After 21 hours,cool the mixture to ambient temperature and stir it overnight. Dilutethe mixture with ethyl acetate and wash the organic layer with 0.1N NaOHand brine. Dry (sodium sulfate) and concentrate the organic layer toresidue. Purify the residue on silica gel using dichloromethane/methanol(90:10) to give 319.7 mg (45%) of a tan foam: mp 173° C. -179° C., dec;mass spectrum (ion spray): m/z=293.1 (M+1).

Example 583 2-(4-Chloro-2-nitro-phenylamino)-benzonitrile

Combine anthranilonitrile (2.36 g, 20 mmol), sodium hydride (1.2 g (60%in oil), 30 mmol) and THF (50 mL), stir at ambient temperature for 30minutes. Add 1-bromo4-chloro-2-nitro-benzene (7.1 g, 30 mmol) and stirat ambient temperature for 3 days. Pour the reaction mixture in ice-coldconcentrated hydrochloric acid (200 mL) and filter the resulting solid.Purify by flash chromatography (dichloromethane) and recrystallize fromhot ethyl acetate to give (1.62 g, 30%) of the title compound as orangeneedles: ¹H NMR (CDCl₃) δ 7.17 (d, 1H), 7.26 (t, 1H), 7.40-7.51 (m, 2H),7.61 (t, 1H), 7.72 (d, 1H), 8.22 (d, 1H), 9.54 (bs, 1H).

Example 584 8-Chloro-5H-dibenzo[b,e][1,4]diazepin-11-ylaminehydrochloride

Combine 2-(4-chloro-2-nitro-phenylamino)-benzonitrile (1.2 g, 4.4 mmol)in ethanol (40 mL) with a solution of stannous chloride dihydrate (2.9g, 13.2 mmol) in 12 N hydrochloric acid (13 mL). Stir and reflux for 2hours, cool to ambient temperature and concentrate. Add water (200 mL),filter and dry to give (890 mg,72%) of the title compound as a yellowsolid: ¹H NMR (DMSO-d₆) δ 6.84-6.69 (m, 5E), 7.27-7.17 (m, 2H), 8.02 (s,1H), 8.83 (bs, 1H), 9.36 (bs, 1H); MS (APCI) m/z (rel intensity) 244.3(100).

Example 58511-(3-(S)-Benzyl-piperazin-1-yl)-8-chloro-5H-dibenzo[b,e][1,4diazepine

Combine 3-(S)-benzyl-piperazine (800 mg, 4.5 mmol),8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride (424 mg,1.5 mmol), toluene (8 mL), dimethylsulfoxide (2 mL) and reflux for 3days. Concentrate and pour into water (50 mL), filtrate the resultingsolid, redissolve in dichloromethane (200 mL), wash with water and dryover magnesium sulfate. After concentration, purify by flashchromatography (dichloromethane then gradient of methanol 3-10%) to give(316 mg, 53%) of the title compound as a yellow foam: mp 79-92° C.; ¹HNMR (CDCl₃): δ 2.59 (dd, 1H), 2.90-2.66 (m, 3H), 3.09-2.94 (m, 3H), 3.85(bm, 1H), 4.03 (bm, 1H), 4.88 (s, 1H), 6.61 (dd, 1H), 6.79-6.84 (m, 2H),6.97 (t, 1H), 7.06 (t, 1H), 7.35-7.19 (m, 7H); MS (APCI) m/z (relintensity) 403.4 (100).

By a method similar to Example 585, using8-chloro-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloride, thefollowing compound was prepared and isolated as the (S) isomer.

No: ArAlk Data 586 CH₂CH₂Ph mp 78-92° C.; ¹H NMR(CDCl₃): δ1.76-1.64(m,2H), 2.74-2.54(m, 4H), 3.07-2.78(m, 4H), 3.84(bm, 1H), 4.00(bm, 1H),4.88(s, 1H), 6.61(dd, 1H), 6.83-6.80(m, 2H), 7.08-6.99(m, 2H),7.32-7.15(m, 7H); MS(APCI)m/z(rel intensity) 417.4(100). 49% yield.

By a similar method to Example 90, the following compounds were preparedand isolated, using 8-Chloro-5H-dibenzo(b,e)(1,4)diazepin-11-ylaminehydrochloride, as the (S) isomer.

No: ArAlk Data 587 CH₂CH₂Ph mp 64-78° C.; ¹H NMR(CDCl₃): δ1.80-1.69(m,1H), 2.00-1.89(m, 1H), 2.28-2.19(m, 1H), 2.35(s, 3H), 2.44-2.34(m, 1H),2.59-2.48(m, 1H), 2.75-2.64(m, 1H), 2.85(d, 1H), 2.93(t, 1H),3.22-3.10(m, 1H), 3.80(bm, 1H), 3.93(bm, 1H), 4.87(s, 1H), 6.61(d, 1H),6.82(dd, 2H), 7.01(dt, 1H), 7.08(d, 1H), 7.21-7.14(m, 3H), 7.33-7.24(m,4H); MS(APCI)m/z(rel intensity) 431.3(90), 270.4(100). 83% yield. 588CH₂Ph mp 69-81° C.; ¹H NMR(CDCl₃): δ2.50-2.39(m, 3H), 2.48(s, 3H),2.94-2.71(m, 2H), 3.24-3.10(m, 2H), 3.51(bm, 1H), 3.85(bm, 1H), 4.83(s,1H), 6.57(dd, 1H), 6.81-6.71(m, 3H), 6.97(s, 1H), 7.25-7.02(m, 7H);MS(APCI)m/z(rel intensity)417.3(100). 96% yield.

Example 589 5-Amino-4-carboxamido-1H-1,2,3-triazole

Dissolve 4-toluenesulphonyl chloride (481.3 g; 2.52 mol) in hot ethanol(2900 ml) and allow the resulting clear solution to cool to roomtemperature. Dissolve sodium azide (198.31 g; 3.05 mol) in water (360ml) and mix the two solutions with stirring. Allow the mixture to standfor one and a half hours at room temperature, pour onto water (7250 ml)and separate the resulting two phase mixture, wash the clear oil withwater, dry over magnesium sulphate and filter to leave the desired4-toluene sulphonyl azide (weight=470.57 g).

Add to the Chem Reactor sodium methoxide in methanol (25% by weight; 470ml) and further methanol (470 ml). Add malonamidine hydrochloride (300g; 2.18 mol) to the solution with stirring. Stir the white slurry formedfor half an hour under nitrogen, cool to 0-5° C. using an ice-waterbath. Add at this temperature, ethanol (3600 ml) and stir the mixturestir for one hour at 10° C. Filter the mixture to remove sodium chlorideand wash the latter with further ethanol (1000 ml). Place the resultantamidine solution back in the Chem Reactor and cool to 5° C. Add thesolution of 4-toluenesulphonyl azide (470.57 g) in ethanol (380 ml) adddropwise over 30 minutes. Stir the mixture at room temperatureovernight, filter and wash with ethanol to leave a white solid, dry at60° C. in a vacuum oven to give5-amino4-carboxamido-1H-1,2,3-triazole=245.6 g (88.6% yield).

Example 590 5-Amino-2-isopropyl-2H-1,2,3-triazole-4-carboxamide

Combine 5-amino-4-carboxamido-1H-1,2,3-triazole (127 g, 1.0 mol) and2-bromopropane (160 g, 1.3 mol) in toluene (1500 ml) and stir at 70° C.for eighteen hours in the presence of 50% aqueous sodium hydroxide (2.0ml) and potassium carbonate (276 g; 2.0 mol) with Adogen 464 (25 g) asthe phase transfer catalyst. After cooling water add and extract theproduct using ethyl acetate. Wash the combined organic phases withwater, dry over magnesium sulphate and remove the solvent in vacuo toleave a residue that is triturated with diethyl ether. Collect the whitesolid by filtration and dry under vacuum at room temperature to give5-amino-2-isopropyl-2H-1,2,3-triazole-4-carboxamide (94.68 g, 56%yield). Alkylation occurs at other positions including the exocyclic NH₂position too varying degrees depending on the alkyl halide used.Normally the 2-substituted product is the major isomer and crystallisesreadily. Chromatography is sometimes necessary. ¹HNMR/c: 1.44 ppm (m,6H), 4.55 ppm (m, 1H), 5.5 ppm (m, 2H), 7.18 ppm (bs, 1H), 7.35 ppm (bs,1H).

Example 591 5-Amino-2-isopropyl-2H-1,2,3-triazole-4-carbonitrile

Add phosphorous oxychloride (99 ml, 1.06 mol) slowly to a stirringsolution of 5-amino-2-isopropyl-2H-1,2,3,-triazole-4-carboxamide (94.68g, 0.56 mol) in anhydrous N,N-dimethylformamide (275 ml). Allow thereaction mixture to stir for three hours, add ice and stir the wholereaction until homogeneous, adjust the to pH 5.5 using ammonia. Extractthe organics with diethyl ether and combine ethereal phases, wash withwater, dry over magnesium sulphate and finally concentrate in vacuo.Dissolve the residue in 2N hydrochloric acid (825 ml) and heat underreflux for 1 hour. Cool the solution in an ice-water bath and filter togive a yellow/white solid. Extract the aqueous phase withdichloromethane (2×500 ml), combine the organic phase, wash with water,dry over magnesium sulphate, filter and evaporate to give an orangesolid. Combine solids and dissolve in dichloromethane and pass through apad of flash silica (500 g) to give a white solid of5-amino-2-isopropyl-2H-1,2,3-triazole-4-carbonitrile (44.2 g, 52%yield): ¹HNMR/c: 1.51 ppm (d, 6H), 4.27 ppm (bs, 2H), 4.62 ppm (m, 1H).

Example 5922-Isopropyl-5-(2-nitroanilino)-2H-1,2,3-triazole-4-carbonitrile

Combine 5-amino-2-isopropyl-2H-1,2,3-triazole-4-carbonitrile (44.2 g,0.292 mol) and 2-fluoronitrobenzene (41.25 g, 0.292 mol) indimethylsulphoxide (590 ml) and stir in the presence of lithiumhydroxide monohydrate (24.56 g;0.584 mol) for eighteen hours at 55° C.Pour the reaction mixture onto ice-water, stir for one hour, filter andwash the filter pad well with water to leave a yellow crystalline solidto give 2-isopropyl-5-(2-nitroanilino)-2H-1,2,3-triazole4-carbonitrile(73.7 g, 93% yield): ¹HNMR/c: 1.6 ppm (d, 6H), 4.8 ppm (m, 1H), 7.05 ppm(tr, 1H), 7.64 ppm (tr, 1H), 8.2 ppm (dd, 1H), 8.28 ppm (dd, 1H), 10.25ppm (s, 1H).

Example 5932-Isopropyl-2,4-dihydro[1,2,3]triazolo[4,5-b][1,5]benzazepin-10-aminehydrochloride

Combine 2-isopropyl-5-(2-nitroanilino)-2H-1,2,3-triazole-4-carbonitrile(51.5 g, 0.1 87 mol) in ethanol (700 ml) and warm to 60° C. Add stannouschloride dihydrate (130 g, 0.561 mol) in 5N hydrochloric acid (700 ml)and add as a single portion and heat the resultant mixture under refluxfor four hours. Chill the reaction mixture overnight to give the productas yellow crystals and collect by filtration and wash with ethanol. Dryat 50° C. under reduced pressure to give2-isopropyl-2,4-dihydro[1,2,3]triazolo[4,5-b][1]benzazepin-10-aminehydrochloride (52.1 g, 100% yield).

Example 594(S)-2-Isopropyl-10-(3-phenethyl-piperazin-1-yl)-2,4-dihydro-1,2,3,4.9-pentaaza-benzo[f]azulenedihydrochloride hemihydrate

Combine2-isopropyl-2,4-dihydro-1,2,3,4,9-pentaaza-benzo[f]azulen-10-ylamine(0.863 g, 3.56 mmol), (S)-2-phenethyl-piperazine (0.678 g, 3.56 mmol) inNMP (6.0 mL) and heat at 200° C. for 3 hours. Cool to ambienttemperature and dilute with water (75 mL). Extract with ethyl acetate togive 1.59 g of the crude product. Silica gel chromatography, eludingwith methylene chloride:methanol (100:7.5), to give the title compoundas the free base. The dihydrochloride salt precipitates in ethyl acetateas a yellow solid: mp 210° C.; mass spectrum (ion spray): m/z=416 (M+1);Analysis for C₂₄H₃₁Cl₂N₇(0.5 H₂O): calcd: C, 57.95; H, 6.48; N, 19.71;found: C, 58.01; H, 6.22; N, 19.70.

Example 595(S)-2-Isopropyl-10-(4-methyl-3-phenethyl-piperazin-1-yl)-2,4-dihydro-1,2,3,4,9-pentaaza-benzo[f]azulenedihydrochloride hemihydrate

Combine(S)-2-isopropyl-10-(3-phenethyl-piperazin-1-yl)-2,4-dihydro-1,2,3,4,9-pentaaza-benzo[f]azulene(0.59 g, 1.42 mmol)and 37% formaldehyde solution (0.13 mL, 1.56 mmol) in1,2-dichloroethane (25 mL). Stir for 10 minutes and add sodiumtriacetoxy borohydride (0.451 g, 2.13 mmol). Stir an additional 30minutes and then pour solution onto saturated sodium bicarbonatesolution. Extract with methylene chloride to give the crude product.Silica gel chromatography, eluding with methylene chloride:methanol(100:2.5), gives the title compound as the free base. Thedihydrochloride salt precipitates in ethyl acetate as a yellow solid:m.p. 200° C.; mass spectrum (ion spray): m/z=430 (M+1); Analysis forC₂₅H₃₃Cl₂N₇(0.5 H₂O): calcd: C, 58.71; H, 6.70; N, 19.17; found: C,58.77; H, 6.60; N, 19.05.

Example 596 (S)-2-(1,4-Dibenzyl-piperazin-2-yl)-1-phenyl-ethanol

Add phenyllithium (11.3 mL, 20.4 mmol, 1.8 M in cyclohexane-ether)dropwise to a −78° C. solution of(S)-(1,4-dibenzyl-piperazin-2-yl)-acetaldehyde (4.2 g, 13.6 mmol) in THF(60 mL). Stir 30 min at −78° C. and 4 h at ambient temperature. Add ice,brine, and extract with ether. Wash the extracts with brine, dry withsodium sulfate, filter and concentrate the filtrate. Purify by silicagel chromatography using 2N ammonia in methanol-methylene chloride(1%-4%) as the eluent to give 3.98 g (76%) of the title compound: massspectrum (ion spray): m/z=387 (M+1). HR-MS calculated for C₂₆H₃₁N₂O:387.2436. Found 387.2442.

Example 597 (S)-1-Phenyl-2-piperazin-2-yl-ethanol

Dissolve (S)-2-(1,4-dibenzyl-piperazin-2-yl)-1-phenyl-ethanol (3.89 g,10.1 mmol) in ethanol (50 mL). Add ammonium formate (3.8 g, 60.4 mmol),palladium hydroxide (1.6 g, 20 wt. % on carbon) and ethanol (25 mL).Heat to reflux. After 6.5 h, cool and stir at ambient temperature 18 h.Filter the palladium hydroxide and concentrate the filtrate. Purify bysilica gel chromatography using 2N ammonia in methanol-methylenechloride (10%) then 7N ammonia in methanol-methylene chloride (10%) asthe eluent to give 860 mg (41%) of the title compound: mass spectrum(ion spray): m/z=207 (M+1).

Example 598 and Example 599(S,R)-2-[4-(2-Methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanol

(S,S)-2-[4-(2-Methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanol

Add methyl trifluoromethanesulfonate (174 μL, 1.53 mmol) to a 0° C.slurry of2-methyl-4,9-dihydro-3-thia-4,9-diaza-benzo[f]azulene-10-thione (315 mg,1.28 mmol) in dichloromethane (4 mL). Stir 1 h at 0° C. then warm toambient temperature and stir 18 h. Concentrate the reaction to an orangepowder. Add (S)-1-phenyl-2-piperazin-2-yl-ethanol (264 mg,1.28 mmol) andpyridine (5 mL). Heat to 110° C. for 5.5 h and stir at ambienttemperature for 18 h. Concentrate the reaction, dissolve the residue inmethanol-dichloromethane, apply to a SCX column. Wash the column withmethanol-dichloromethane to remove impurities then elute the productwith 2N ammonia in methanol-dichloromethane (10%). Concentrate andpurify by radial silica gel chromatography using a 2 mm plate and 2Nammonia in methanol-methylene chloride (2.5%-3%) as the eluent to give39 mg of(S,R)-2-[4-(2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanoland 130 mg of(S,S)-2-[4-(2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanol.

(S,R)-2-[4-(2-Methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanol:mass spectrum (ion spray): m/z=419 (M+1). HR-MS calculated forC₂₄H₂₇N₄OS: 419.1906. Found 419.1919. ¹H NMR (DMSO-d6): δ 7.55 (s, 1H),7.37-7.26 (m, 4H), 7.25-7.17 (m, 1H), 6.87-6.73 (m, 3H), 6.67 (br d,1H), 6.30 (s, 1H), 5.52 (br s, 1H), 4.75-4.66 (m, 1H), 3.84 (br d, 1H),3.72 (br d, 1H), 2.88 (d, 1H), 2.82-2.60 (m, 3H), 2.56-2.45 (m, 1H),2.41 (br s, 1H), 2.26 (s, 3H), 1.50-1.73 (m, 2H).

(S,S)-2-[4-(2-Methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanol:mass spectrum (ion spray): m/z=419 (M+1). HR-MS calculated forC₂₄H₂₇N₄OS: 419.1906. Found 419.1909. ¹H NMR (DMSO-d₆): δ 7.56 (s, 1H),7.37-7.15 (m, 5H), 6.87-6.74 (m, 3H), 6.67 (br d, 1H), 6.31 (s, 1H),5.29 (br s, 1H), 4.74-4.67 (m, 1H), 3.88 (br d, 1H), 3.80 (br d, 1H),2.86 (d, 1H), 2.80-2.59 (m, 3H), 2.53-2.42 (m, 2H), 2.28 (s, 3H),1.62-1.53 (m, 2H).

Example 600(S,S)-2-[1-Methyl-4-(2-methyl-4H-3-thia-4,9-diazabenzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanol

Add formaldehyde (33 μL, 0.42 mmol, 37% in water) to a solution of(S,S)-2-[4-(2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulen-10-yl)-piperazin-2-yl)-1-phenyl-ethanol(160 mg, 0.38 mmol) in methylene chloride (6 mL). Stir 15 min at ambienttemperature. Add sodium triacetoxyborohydride (121 mg, 0.57 mmol) andstir 2 h at ambient temperature. Dilute with saturated sodiumbicarbonate solution and extract with methylene chloride. Dry theextracts with sodium sulfate, filter and concentrate the filtrate.Purify by radial silica gel chromatography using a 2 mm plate and 2Nammonia in methanol-methylene chloride (1%-5%) as the eluent to give 70mg (42%) of the title compound: mass spectrum (ion spray): m/z=433(M+1), 431 (M−1). HR-MS calculated for C₂₅H₂₉N₄OS: 433.2062. Found433.2061. ¹H NMR (DMSO-d₆): δ 7.60 (s, 1H), 7.36-7.17 (m, 5H), 6.88-6.75(m, 3H), 6.68 (br d, 1H), 6.35 (s, 1H), 5.34 (br d, 1H), 4.60-4.50 (m,1H), 3.85 (br d, 1H), 3.70 (br d, 1H), 3.04-2.92 (m, 1H), 2.85-2.66 (m,2H), 2.29 (s, 3H), 2.17 (s, 3H), 2.20-2.10 (m, 1H) 2.08-1.98 (m, 1H),1.97-1.85 (m, 1H), 1.66-1.52 (m, 1H).

Example 601 and Example 602(S,R)-2-[4-(2-Isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanol

(S,S)-2-[4-(2-Isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanol

Add methyl trifluoromethanesulfonate (806 μL, 7.13 mmol) to a 0° C.slurry of2-isopropyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo[f]azulene-10-thione(1.31 g, 4.75 mmol) in dichloromethane (15 mL). Stir 18 h, graduallyallowing reaction to warm to ambient temperature. Concentrate thereaction to an orange powder. Add (S)-1-phenyl-2-piperazin-2-yl-ethanol(980 mg, 4.75 mmol) and pyridine (11 mL). Heat to 115° C. for 5 h.Concentrate and purify by silica gel chromatography using 2N ammonia inmethanol-methylene chloride (0%-10%) then 7N ammonia inmethanol-methylene chloride (20%) as the eluent to give 520 mg. Purifyagain, in two portions, by radial silica gel chromatography using a 2 mmplate and 2N ammonia in methanol-methylene chloride (2.5%-4.5%) as theeluent to give 28 mg of(S,R)-2-[4-(2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanoland 155 mg of(S,S)-2-[4-(2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanolafter combining both radial purifications.

(S,R)-2-[4-(2-Isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanol:mass spectrum (ion spray): m/z=448 (M+1), 446 (M−1). HR-MS calculatedfor C₂₅H₃₀N₅OS: 448.2171. Found 448.2181.¹H NMR (DMSO-d₆): δ 7.78 (s,1H), 7.37-7.16 (m, 5H), 6.89-6.73 (m, 3H), 6.67 (br d, 1H), 5.44 (br s,1H), 4.74-4.67 (m, 1H), 4.04-3.87 (m, 2H), 3.05 (quintet, 1H), 2.93-2.79(m, 2H), 2.76-2.54 (m, 3H), 1.73-1.60 (m, 1H), 1.59-1.47 (m, 1H), 1.21(d, 6H).

(S,S)-2-[4-(2-Isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanol:mass spectrum (ion spray): m/z=448 (M+1), 446 (M−1). HR-MS calculatedfor C₂₅H₃₀N₅OS: 448.2171. Found 448.2156. ¹H NMR (DMSO-d₆): δ 7.80 (s,1H), 7.35-7.16 (m, 5H), 6.90-6.74 (m, 3H), 6.68 (br d, 1H), 5.44 (br s,1H), 4.75-4.63 (m, 1H), 4.19-3.89 (m, 2H), 3.08 (quintet, 1H), 2.90-2.50(m, 5H), 1.64-1.51 (m, 2H), 1.23 (d, 6H).

Example 603(S,S)-2-[4-(2-Isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-yl)-1-methyl-piperazin-2-yl]-1-phenyl-ethanol

Add formaldehyde (23 μL, 0.29 mmol, 37% in water) to a solution of(S,S)-2-[4-(2-isopropyl-4H-3-thia-1,4,9-triaza-benzo[f]azulen-10-yl)-piperazin-2-yl]-1-phenyl-ethanol(117 mg, 0.26 mmol) in dichloroethane (5 mL). Stir 15 min at ambienttemperature. Add sodium triacetoxyborohydride (83 mg, 0.39 mmol) andstir 2 h at ambient temperature. Dilute with saturated sodiumbicarbonate solution and extract with methylene chloride. Dry theextracts with sodium sulfate, filter and concentrate the filtrate.Purify by radial silica gel chromatography using a 2 mm plate and 2Nammonia in methanol-methylene chloride (1%-4%) as the eluent to give 68mg (56%) of the title compound: mass spectrum (ion spray): m/z=462(M+1), 460 (M−1). HR-MS calculated for C₂₆H₃₂N₅OS: 462.2328. Found462.2322. ¹H NMR (DMSO-d6): δ 7.82 (s, 1H), 7.35-7.18 (m, 5H), 6.91-6.76(m, 3H), 6.69 (br d, 1H), 5.29 (s, 1H), 4.58-4.46 (m, 1H), 4.14-3.77 (m,2H), 3.02-3.17 (m, 2), 2.90 (dd, 1H), 2.74-2.65 (m, 1H), 2.28-2.11 (m,1H), 2.14 (s, 3H), 2.03-1.84 (m, 2H) 1.70-1.54 (m, 1H), 1.26 (d, 6H).

Example 604 2-(2-Nitro-phenylamino)-5-trifluoromethyl-benzonitrile

Add cesium carbonate (1.3 g, 4 mmol) to a solution of 2-nitro-aniline(276 mg, 2 mmol) and 2-fluoro-5-trifluoromethyl-benzonitrile (378 mg, 2mmol) in DMF (10 mL) at room temperature then stir the resulting darkred solution at room temperature for 16 hours and 2 hours at 50° C. Cooldown and pour into a mixture of ice and concentrated hydrochloric acid(50 mL, v/v). Extract the aqueous phase with dichloromethane (3×300 mL),wash with water and brine and dry over MgSO₄ to yield the titledcompound as a yellow solid (480 mg, 80%): mp 160-161° C.; ¹H NMR (CDCl₃)δ 7.14 (ddd, 1H), 7.48 (dd, 1H), 7.58 (dd, 1H), 7.60 (d, 1H), 7.76 (dd,1H), 7.92 (d, 1H), 8.27 (dd, 1H), 9.63 (bs, 1H). MS (ES/neg) m/z (relintensity) 306.1 (100).

Example 605 2-Trifluoromethyl-5H-dibenzo[b,e][1,4]diazepin-11-ylaminehydrochloride salt

Add a solution of tin(II) chloride (567 mg, 3 mmol) in 12 N hydrochloricacid (1.8 mL) to a solution of2-(2-nitro-phenylamino)-5-trifluoromethyl-benzonitrile (307 mg, 1 mmol)in ethanol (10 mL). Reflux for 24 hours, then concentrate under vacuum,add water and filter. Wash the resulting solid with water anddichloromethane then dry under vaccum to yield the titled compound as ayellow solid (282 mg, 90%): mp 334-336° C.; ¹H NMR (DMSO-d₆) δ 7.05-7.19(m, 4H), 7.34 (d, 1H), 7.86 (dd, 1H), 7.87 (s, 1H), 8.79 (s, 1H), 9.26(s, 1H), 9.75 (s, 1H), 12.40 (s, 1H). MS (ESI/neg) m/z (rel intensity)276.1 (100).

Example 60611-(4-Methyl-piperazin-1-yl)-2-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepine

By a method similar to Example 59,2-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepin-11-ylamine hydrochloridesalt (600 mg, 1.9 mmol) and N-methyl piperazine (960 mg, 9.6 mmol)afforded the title compound as a yellow solid (555 mg, 81%): mp 68-72°C.; ¹H NMR (CDCl₃) δ 2.36 (s, 3H), 2.53 (bs, 4H), 3.42 (m, 4H), 5.12 (s,1H), 6.70 (d, 1H), 6.90 (d, 1H), 6.92 (dt, 1H), 7.01 (dd, 1H), 7.10 (d,1H), 7.52 (d, 1H), 7.55 (s, 1H); ¹⁹F NMR (CDCl₃) δ −328.38; MS (ESI/neg)m/z (rel intensity) 359.2 (100).

Example 6072-(4-Fluoro-2-nitro-phenylamino)-5-trifluoromethyl-benzonitrile

Combine 4-fluoro-2-nitro-phenylamine (5.9 g, 32.03 mmol),2-fluoro-5-trifluoromethyl-benzonitrile (6.07 g, 32.03 mmol) and lithiumhydroxide monohydrate (4.03 g, 96.08 mmol) in methyl sulfoxide (DMSO, 60ml). Heat the resulting mixture to 70° C. for 16 hours. Cool thereaction mixture to ambient temperature, then pour into approximately400 ml of ice water and stir for one hour. Filter the resulting mixtureand collect the precipitate. Obtained 9.995 g of the title compound(30.73 mmol, 96% yield) as an orange amorphous solid. Product used as iswith no further purification: Mass Spectrum (m/e): 326(M+1).

Example 6088-Fluoro-2-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepin-11-ylaminehydrochloride

Heat a solution of2-(4-fluoro-2-nitro-phenylamino)-5-trifluoromethyl-benzonitrile (9.995g, 30.73 mmol) in ethanol (170 ml) to 60° C. Add to a solution of tin(II) chloride (29.1 g, 153.67 mmol) in 5.0 N hydrochloric acid (170 ml)and heat to reflux. After 18 hours, cool the reaction to roomtemperature and place in a freezer for 24 hours. The productprecipitates from the solution and is collected by filtration. Obtained2.253 g of the title compound (6.79 mmol, 22% yield) as a yellowamorphous solid: Mass Spectrum (m/e): 296(M+1).

Example 6098-Fluoro-11-{3-[2-(4-methoxy-phenyl)-ethyl]-piperazin-1-yl}-2-trifluoromethyl-5H-dibenzo[b,e][1,4diazepinesuccinate

Heat a solution of8-fluoro-2-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepin-11-ylaminehydrochloride (0.2 g, 0.60 mmol) and diisopropylethylamine (0.086 g,0.66 mmol) in 1-methyl-2-pyrrolidinone (4mL) to 60° C. for 30 minutes.Add 2-[2-(4-methoxy-phenyl)-ethyl]-piperazine (0.398 g, 1.81 mmol) andheat the reaction mixture to 195° C. for 14 hours. Cool reaction mixtureto ambient temperature. Dilute with 50 ml of ethyl acetate and washtwice with saturated aqueous sodium chloride then twice with water.Collect the organic layer and dry over sodium sulfate. Remove solventunder reduced pressure. Purification via flash chromatography, elutingwith a linear gradient starting with 100% dichloromethane and going to85% dichloromethane with 15% 2M ammonia in methanol, gives the free baseof the title compound (0.107 g, 0.21 mmol, 36% yield) as a yellowamorphous solid. Convert the product to the succinate salt by dissolvingthe product in methanol and adding one equivalent of succinic acid,swirl or sonicate the mixture until no solid succinic acid remains, thenremoving the solvent under reduced pressure gives the title compound:Mass Spectrum (m/e): 499(M+1); Exact Mass Spec: Calc. 499.2121; Found499.2136.

Example 6108-Fluoro-11-{3-[2-(4-methoxy-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-bifluoromethyl-5H-dibenzo[b,e][1,4]diazepine

Dissolve the free base obtained from Example 609 (0.078 g, 0.16 mmol) indichloromethane (8 ml). Add sodium triacetoxyborohydride (0.066 g, 0.31mmol) and formaldehyde (0.005 g, 0.16 mmol, 0.013 g of a 37% aqueoussolution) and stir the mixture for two hours at ambient temperature.Dilute the mixture with saturated aqueous sodium chloride (50 mL) andextract three times with dichloromethane. Combine the organic layers,dryover sodium sulfate and remove the solvent under reduced pressure.Purification via flash chromatography, eluting with a linear gradientstarting with 100% of a stock mixture of 80% dichloromethane with 20%hexanes and going to 85% of the stock mixture with 15% 2M ammonia inmethanol, gives the free base of the title compound (0.062 g, 0.12 mmol,77% yield) as a yellow amorphous solid. It is then converted to thesuccinate salt as described previously: Mass Spectrum (m/e): 513(M+1);Exact Mass Spec: Calc. 513.2278; Found 513.2284.

Example 6118-Fluoro-11-{3-[2-(4-fluoro-phenyl)-ethyl]-piperazin-1-yl}-2-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepine

Heat a solution of8-fluoro-2-trifluoromethyl-5H-dibenzo[b,e][1,4]diazepin-11-ylaminehydrochloride (0.2 g, 0.60 mmol) and diisopropylethylamine (0.086 g,0.66 mmol) in 1-methyl-2-pyrrolidinone (4 mL) to 60° C. After 30minutes, add 2-[2-(4-fluoro-phenyl)-ethyl]-piperazine (0.38 g, 1.81mmol) and heat the reaction mixture to 195° C. for 16 hours. Coolreaction mixture to ambient temperature. Dilute with of ethyl acetate(50 ml) and wash twice with saturated aqueous sodium chloride then twicewith water. Collect the organic layer and dry over sodium sulfate.Remove solvent under reduced pressure. Purification via flashchromatography, eluting with a linear gradient starting with 100%dichloromethane and going to 85% of dichloromethane with 15% 2M ammoniain methanol, gives the free base of the title compound (0.083 g, 0.17mmol, 28% yield) as a yellow amorphous solid: Mass Spectrum (m/e):487(M+1).

Example 6128-Fluoro-1-{3-[2-(4-fluoro-phenyl)-ethyl]-4-methyl-piperazin-1-yl}-2-trifluoromethyl-5H-dibenzo[b,e][1,4diazepine

Dissolve the product obtained from Example 611 (0.083 g, 0.17 mmol) indichloromethane (8 ml). Add sodium triacetoxyborohydride (0.072 g, 0.34mmol) and formaldehyde (0.005 g, 0.17 mmol, 0.014 g of a 37% aqueoussolution) and stir the mixture for two hours at ambient temperature.Dilute the mixture with of saturated aqueous sodium chloride (50 mL) andextract three times with dichloromethane. Combine the organic layers,dry over sodium sulfate and remove the solvent under reduced pressure.Purification via flash chromatography, eluting with a linear gradientstarting with 100% of dichloromethane and going to 85% dichloromethanewith 15% 2M ammonia in methanol, gives the free base of the titlecompound (0.032 g, 0.06 mmol, 37% yield) as a yellow amorphous solid. Itis then converted to the succinate salt as described previously: MassSpectrum (m/e): 501(M+1); Exact Mass Spec. Calc 501.2078; Found501.2093.

Receptor Binding Assays

Serotonin 5-HT₆ and Dopamine D₂ Binding Assay Protocol

The assay buffers used are 50 mM Tris-HCl pH 7.4, 120 mM NaCl, 5 mM KCl,5 mM MgCl₂, 1 mM EDTA for the Dopamine D₂s receptor binding assay. Theradioligand used is [¹²⁵I]iodospiperone from New England Nuclear Cat#NEX284-2200 Ci/mmole. The membranes used are from Receptor Biology (nowowned by NEN), Cat #RBHD2CM for the D₂ receptor.

Compounds are obtained as 10 mM stocks in 100% DMSO. They are diluted to1 mM in 100% DMSO by adding 180 μL DMSO to 20 μL of stock in 96 wellplates using a multidrop. The 1 mM stocks are then diluted to make an 11point concentration range from 125 μM down to 1.25 μM in half logincrements using 10% DMSO as diluent. This is done using a TECAN robot.The final DMSO at this stage is 10-21.25% DMSO

The radioligand is diluted in assay buffer to provide 0.1 nM for the D₂assay. Each vial of membranes is diluted up to 92 mL in assay buffer.The final assay volume is 250 μL consisting of 210 μl of dilutedmembranes, 20 μL of compound or 10% DMSO for total binding, and 20 μL ofdiluted radioligand. The compounds are transferred from drug dilutionplates into coming 96 well assay plates using a 96 well Multimekpipettor. Radioligand and membranes are added to assay plates usingmultidrop pipettors. Non-specific binding is determined in wellscontaining a final concentration of 5 μM haloperidol. The final drugconcentration range in half logs is from 10 μM down to 0.1 nM. The finalDMSO in the assay is 1-1.7%.

After addition of drug, membrane, and ligand, the plates are incubatedfor 2 hours at room temperature. During this time 96 well Milliporefilter plates (MAFBNOB50) are soaked for a least 30 minutes with 200 μLper well of 0.5% polyethyleneimine.

The 0.5% PEI is removed from filterplate wells using a TiterTek MAPaspirator and 200 μL of the incubation mixture is transferred from theincubation plate to the filterplate after mixing. This transfer is doneusing the 96 tip Mutimek pipettor. After transfer to the filterplatefilterplates are extracted and ished twice with 220 μL per well of coldbuffer on the MAP aspirator. The peel away bottoms are removed from thefilterplates and 60 μL per well of microscint 20 scintillation fluid isadded per well using a multidrop. Plates are placed into suitableholders and are left at room temperature for 3 hours and are counted for³H in either a Wallac Microbeta counter or on a Packard Topcount.

[¹²⁵I]DOI SPA Binding to Rhesus 5-HT_(2A) Receptors Protocol

Incubations are performed in a total volume of 200 μl in 96 well assayplates. 50 μL [¹²⁵I]DOI (NEN, 2200 Ci/mmol, final concentration=0.075nM)is added to 50 μL of test compounds dissolved in water (±DMSO and/orglacial acetic acid). 50 μL Wheat Germ Agglutinin (WGA) SPA beads, at 1mg/well, (Amersham Life Sciences) in assay buffer (67mM Tris-HCl pH 7.4,1 3mM MgCl₂, 0.67 mM EDTA) are then added. Membrane homogenate fromcells expressing rhesus 5-HT_(2A) receptors, approximately 0.9 millioncells/well, is added last. The plates are covered with sealing tape(FasCal) and allowed to incubate at room temperature for 2 hours. Theplates are then centrifuged at approximately 200× g for 10 minutes atroom temperature. The amount of ¹²⁵I-DOI bound to the membranes, i.e.proximate to the WGA SPA beads, is then determined using a WallacMicroBeta Trilux Scintillation Counter (Wallac, Inc.).

Pharmaceutical Formulations

Capsule

A pulvule formulation is prepared by blending the active with siliconestarch, and filling it into hard gelatin capsules. Per 300 mg capsuleCompound of formula (I)  5.0 mg Silicone  2.9 mg Starch flowable 292.1mgTablet

A tablet formulation is made by granulating the active with appropriatediluent, lubricant, disintegrant and binder and compressing. Per 300 mgtablet Compound of formula (I)  10.0 mg Magnesium stearate  0.9 mgMicrocrystalline cellulose  75.0 mg Povidone  15.0 mg Starch, directlycompressible 199.1 mgInjection

An aqueous injection of active is prepared as a freeze-dried plug, forreconstitution in a suitable, sterile diluent before use (to a totalvolume of 10 ml). Compound of formula (I) 20.0 mg Mannitol 20.0 mg NHydrochloric acid and/or N sodium hydroxide to adjust pH to 5-5.5.Controlled Release Injection

A controlled release injection for intramuscular injection is formedfrom a sterile suspension of micronised active in an oleaginous vehicle.Compound of formula (I) 65.0 mg Aluminium stearate 0.04 mg Sesame oil  2 ml

1. A compound of formula (I):

wherein, A is an optionally benzo-fused five or six member aromatic ring having zero to three hetero atoms independently selected from N, O, and S; Alk is (C₁₋₄) alkylene optionally substituted with OH, methoxy, ethoxy, or F; Ar is optionally substituted phenyl, naphthyl, monocyclic heteroaromatic, or bicyclic heteroaromatic; R¹ is hydrogen or (C₁₋₄) alkyl optionally substituted with OH, OR³, or OCH₂CH₂OH, wherein R³ is (C₁₋₂) alkyl; R² is H, (C₁₋₆) alkyl, halogen, fluorinated (C₁₋₆) alkyl, OR⁴, SR⁴, NO₂, CN, COR⁴, CONR⁵R⁶, SO₂NR⁵R⁶, NR⁵R⁶, NR⁵COR⁴, NR⁵SO₂R⁴, or optionally substituted phenyl, wherein R⁴ is hydrogen, (C₁₋₆) alkyl, fluorinated (C₁₋₆) alkyl, benzyl, or optionally substituted phenyl, R⁵ and R⁶ are independently hydrogen, (C₁₋₆) alkyl, or optionally substituted phenyl; Z is one or two substituents independently selected from hydrogen, halogen, (C₁₋₆) alkyl, fluorinated (C₁₋₆) alkyl, OR⁷, SR⁷, NO₂, CN, COR⁷, CONR⁸R⁹, SO₂NR⁸R⁹, NR⁸SO₂R⁷, NR⁸R⁹, or optionally substituted phenyl, wherein R⁷ is hydrogen, (C₁₋₆) alkyl, fluorinated (C₁₋₆) alkyl, benzyl, or optionally substituted phenyl, R⁸ and R⁹ are independently hydrogen, (C₁₋₆) alkyl, or optionally substituted phenyl; and salts, solvates, and crystal forms thereof.
 2. A compound of formula (I):

wherein, A is an optionally benzo-fused five or six member aromatic ring having zero to three hetero atoms independently selected from N, O, and S; Alk is (C₁₋₄) alkylene optionally substituted with OH; Ar is optionally substituted phenyl, naphthyl, monocyclic heteroaromatic, or bicyclic heteroaromatic; R¹ is hydrogen or (C₁₋₄) alkyl; R² is H, (C₁₋₆) alkyl, halogen, or fluorinated (C₁₋₆) alkyl; Z is one or two substituents independently selected from hydrogen, or halogen; and salts, solvates, and crystal forms thereof.
 3. The compounds of claim 1 wherein the aromatic ring A is selected from the group consisting of:


4. Compounds of claim 1 in which Alk is —CH₂— or —CH₂CH₂—.
 5. Compounds of claim 1 in which Ar is optionally substituted phenyl, furan, or thiophene.
 6. Compounds of claim 1 in which R¹ is hydrogen, methyl, or —CH₂CH₂—O—CH₂CH₂—OH.
 7. Compounds of claim 1 in which R² is hydrogen, (C₁₋₆) alkyl, fluorinated (C₁₋₆) alkyl, or halogen.
 8. Compounds of claim 1 in which Z is hydrogen or halogen.
 9. Compounds of claim 1 in which the stereo configuration is “S” about the carbon of the piperazine group bound to Alk.
 10. Compounds of claim 1 in which the stereo configuration is “R” about the carbon of the piperazine group bound to Alk.
 11. A compound of claim 1 included in Table 1: TABLE 1 (If)

E₁ E₂ E₃ Alk Ar R¹ R² Z CH C S CH₂CH₂Ph H CH₃ H CH C S CH₂Ph H CH₃ H CH C S CH₂(4-OCH₂CH═C(CH₃)₂)Ph H CH₃ H CH C S CH₂(3,4-OCH₂O-)Ph H CH₃ H CH C S CH₂(3,4-diOCH₃)Ph H CH₃ H CH C S CH₂(4-iPr)Ph H CH₃ H CH C S CH₂(4-PhO)Ph H CH₃ H CH C S CH₂(napthalen-2-yl) H CH₃ H CH C S CH₂(napthalen-1-yl) H CH₃ H CH C S CH₂(4-CH₃)Ph H CH₃ H CH C S CH₂(3-CH₃)Ph H CH₃ H CH C S CH₂(2-F)Ph H CH₃ H CH C S CH₂(3-F)Ph H CH₃ H CH C S CH₂(4-F)Ph H CH₃ H CH C S CH₂(2-CF₃)Ph H CH₃ H CH C S CH₂(2-OCH₃)Ph H CH₃ H CH C S CH₂(3-OCH₃)Ph H CH₃ H CH C S CH₂(4-OCH₃)Ph H CH₃ H CH C S CH₂(3,4-diCl)Ph H CH₃ H CH C S CH₂(indol-3-yl) H CH₃ H CH C S CH₂(thiophen-2-yl) H CH₃ H CH C S CH₂(benzo(b)thiophen-3-yl) H CH₃ H CH C S CH₂(3-O-i-Pr)Ph H CH₃ H CH C S (R)CH₂Ph H CH₃ H CH C S CH₂(2,4-DiOCH₃)Ph H CH₃ H CH C S CH₂(4-Cl)Ph H CH₃ H CH C S CH₂(2-Cl)Ph H CH₃ H CH C S CH₂(3-Cl)Ph H CH₃ H CH C S CH₂(3,5-DiF)Ph H CH₃ H CH C S CH₂(3-CF₃)Ph H CH₃ H CH C S CH₂CH₂Ph CH₃ CH₃ H CH C S CH₂Ph CH₃ CH₃ H CH C S CH₂(4-O—CH₂CH═CH₂)Ph CH₃ CH₃ H CH C S CH₂(pyridin-2-yl) CH₃ CH₃ H CH C S (R)CH₂Ph CH₃ CH₃ H CH C S CH₂(napthalen-2-yl) CH₃ CH₃ H CH C S CH₂(napthalen-1-yl) CH₃ CH₃ H CH C S CH₂(4-CH₃)Ph CH₃ CH₃ H CH C S CH₂(3-CH₃)Ph CH₃ CH₃ H CH C S CH₂(2-F)Ph CH₃ CH₃ H CH C S CH₂(3-F)Ph CH₃ CH₃ H CH C S CH₂(4-F)Ph CH₃ CH₃ H CH C S CH₂(3-CF₃)Ph CH₃ CH₃ H CH C S CH₂(2-CF₃)Ph CH₃ CH₃ H CH C S CH₂(2-OCH₃)Ph CH₃ CH₃ H CH C S CH₂(3-OCH₃)Ph CH₃ CH₃ H CH C S CH₂(4-OCH₃)Ph CH₃ CH₃ H CH C S CH₂(3,4-diCl)Ph CH₃ CH₃ H CH C S CH₂(indol-3-yl) CH₃ CH₃ H CH C S CH₂(thiophen-2-yl) CH₃ CH₃ H CH C S CH₂(benzo(b)thiophen-3-yl) CH₃ CH₃ H CH C S CH₂(2-Cl)Ph CH₃ CH₃ H CH C S CH₂(3-Cl)Ph CH₃ CH₃ H CH C S CH₂(4-Cl-Ph) CH₃ CH₃ H CH C S CH₂(4-OPh)Ph CH₃ CH₃ H CH C S CH₂(3-OPh)Ph CH₃ CH₃ H CH C S CH₂(3-O-iPr)Ph CH₃ CH₃ H CH C S CH₂(2,4-di OCH₃)Ph CH₃ CH₃ H CH C S CH₂CH₂(2-pyridin-2-yl) H CH₃ H CH C S CH₂CH₂(2-pyridin-4-yl) H CH₃ H CH C S CH₂CH₂(4-F)Ph H CH₃ H CH C S CH₂CH₂(3-F)Ph H CH₃ H CH C S CH₂CH₂(2-F)Ph H CH₃ H CH C S CH₂CH₂(4-OCH₃)Ph H CH₃ H CH C S CH₂CH₂(3-OCH₃)Ph H CH₃ H CH C S CH₂CH₂(2-OCH₃)Ph H CH₃ H CH C S CH₂CH₂(4-F)Ph CH₃ CH₃ H CH C S CH₂CH₂(3-F)Ph CH₃ CH₃ H CH C S CH₂CH₂(2-F)Ph CH₃ CH₃ H CH C S CH₂CH₂(4-OCH₃)Ph CH₃ CH₃ H CH C S CH₂CH₂(3-OCH₃)Ph CH₃ CH₃ H CH C S CH₂CH₂(2-OCH₃)Ph CH₃ CH₃ H CH C S CH₂CH₂(2-pyridin-4-yl) CH₃ CH₃ H CH C S CH₂CH₂(2-pyridin-3-yl) H CH₃ H CH C S CH₂CH₂(2-pyridin-3-yl) CH₃ CH₃ H CH C S CH₂CH₂(2-pyridin-2-yl) CH₃ CH₃ H CH C S (CH₂)₄Ph H CH₃ H CH C S (CH₃)₄Ph CH₃ CH₃ H CH C S (CH₃)₃Ph H CH₃ H CH C S (CH₃)₃Ph CH₃ CH₃ H CH C S CH₂(4-Br)Ph H CH₃ H CH C S CH₂(4-I)Ph H CH₃ H CH C S CH₂(4-O—CH₂CH═CH₂)Ph H CH₃ H CH C S CH₂(thiophen-3-yl) H CH₃ H CH C S CH₂(4-O-isoPropyl)Ph H CH₃ H CH C S CH₂(4-Br)Ph CH₃ CH₃ H CH C S CH₂(thiophen-3-yl) CH₃ CH₃ H CH C S CH₂(4-I)Ph CH₃ CH₃ H CH C S CH₂(4-O-isoPropyl)Ph CH₃ CH₃ H CH C S CH₂(3,5-DiCH₃)Ph H CH₃ H CH C S CH₂(4-O-CH₂C(═CH₂)CH₃)Ph H CH₃ H CH C S CH₂(2-OCH₂CH₃)Ph H CH₃ H CH C S CH₂(2-O-iPr)Ph H CH₃ H CH C S CH₂(pyridin-2-yl) H CH₃ H CH C S CH₂(3-OPh)Ph H CH₃ H CH C S CH₂(4-O-CH₂CH═C(CH₃)₂)Ph CH₃ CH₃ H CH C S CH₂(3,4-OCH₂O-)Ph CH₃ CH₃ H CH C S CH₂(3,4-Di(OCH₃))Ph CH₃ CH₃ H CH C S CH₂(4-O-CH₂C(═CH₂)CH₃)Ph CH₃ CH₃ H CH C S CH₂(4-isoPropyl)Ph CH₃ CH₃ H CH C S CH₂(3,5-Di(CH₃))Ph CH₃ CH₃ H CH C S CH₂(2-OCH₂CH₃)Ph CH₃ CH₃ H CH C S CH₂(4-Ph)Ph CH₃ CH₃ H CH C S CH₂(2-O-isoPropyl)Ph CH₃ CH₃ H CH C S CH₂CH₂(3-Cl)Ph H CH₃ H CH C S CH₂CH₂(4-Cl)Ph H CH₃ H CH C S CH₂CH₂(2-Cl)Ph H CH₃ H CH C S CH₂CH₂(4-Cl)Ph CH₃ CH₃ H CH C S CH₂CH₂(3-Cl)Ph CH₃ CH₃ H CH C S CH₂CH₂(2-Cl)Ph CH₃ CH₃ H CH C S CH₂CH₂(4-CF₃)Ph H CH₃ H CH C S CH₂CH₂(2-CF₃)Ph H CH₃ H CH C S CH₂CH₂(3-CF₃)Ph H CH₃ H CH C S CH₂CH₂(4-CF₃)Ph CH₃ CH₃ H CH C S CH₂CH₂(2-CF₃)Ph CH₃ CH₃ H CH C S CH₂CH₂(3-CF₃)Ph CH₃ CH₃ H CH C S CH₂CH₂(2,4-diF)Ph H CH₃ H CH C S CH₂CH₂(2,4-diF)Ph CH₃ CH₃ H CH C S CH₂CH₂(3-F)Ph H CH₃ 6F CH C S CH₂CH₂(4-OCH₃)Ph H CH₃ 6F CH C S CH₂CH₂(3-F)Ph H CH₃ 7F CH C S CH₂CH₂(4-OCH₃)Ph H CH₃ 7F CH C S CH₂CH₂(3-F)Ph CH₃ CH₃ 6F CH C S CH₂CH₂(4-OCH₃)Ph CH₃ CH₃ 6F CH C S CH₂CH₂(3-F)Ph CH₃ CH₃ 7F CH C S CH₂CH₂(4-OCH₃)Ph CH₃ CH₃ 7F CH C S CH₂CH₂(3-F)Ph H CH₂CH₃ 7F CH C S CH₂CH₂(3-F)Ph CH₃ CH₂CH₃ 7F CH C S CH₂CH₂(4-OCH₃)Ph H CH₂CH₃ 7F CH C S CH₂CH₂(4-OCH₃)Ph CH₃ CH₂CH₃ 7F CH C S CH₂CH₂(2-napthalen-1-yl) H CH₃ H CH C S CH₂CH₂(2-napthalen-1-yl) CH₃ CH₃ H CH C S CH₂CH₂(2-napthalen-2-yl) H CH₃ H CH C S CH₂CH₂(2-napthalen-2-yl) CH₃ CH₃ H CH C S CH₂CH₂(2-furan-3-yl) H CH₃ H CH C S CH₂CH₂(2-furan-3-yl) CH₃ CH₃ H CH C S CH₂CH₂(2-thiophene-3-yl) H CH₃ H CH C S CH₂CH₂(2-thiophene-3-yl) CH₃ CH₃ H CH C S CH₂Ph H CH(CH₃)2 H CH C S CH₂CH₂Ph H CH(CH₃)₂ H CH C S CH₂(2-OCH₃)Ph H CH(CH₃)₂ H CH C S CH₂CH₂Ph CH₃ CH(CH₃)₂ H CH C S CH₂Ph CH₃ CH(CH₃)₂ H CH C S CH₂(2-OCH₃)Ph CH₃ CH(CH₃)2 H CH C S CH₂CH₂Ph H C(CH₃)₃ H CH C S CH₂CH₂Ph CH₃ C(CH₃)₃ H N C S CH₂CH₂Ph H CH₃ H N C S CH₂CH₂Ph CH₃ CH₃ H N C S CH₂Ph H CH₃ H N C S CH₂(2-OCH₃)Ph H CH₃ H N C S CH₂CH₂(4-OCH₃)Ph H CH₃ H N C S CH₂CH₂(4-OCH₃)Ph CH₃ CH₃ H N C S CH₂CH₂(4-F)Ph H CH₃ H N C S CH₂CH₂(3-F)Ph H CH₃ H N C S CH₂CH₂Ph H CH(CH₃)₂ H N C S CH₂CH₂(4-OCH₃)Ph H CH(CH₃)₂ H N C S CH₂Ph H CH(CH₃)₂ H N C S CH₂CH₂(3-F)Ph H CH(CH₃)2 H N C S CH₂CH₂(4-F)Ph H CH(CH₃)₂ H N C S CH₂Ph CH₃ CH₃ H N C S CH₂(2-OCH₃)Ph CH₃ CH₃ H N C S CH₂CH₂Ph CH₃ CH(CH₃)₂ H N C S CH₂CH₂(4-OCH₃)Ph CH₃ CH(CH₃)₂ H N C S CH₂Ph CH₃ CH(CH₃)₂ H N C S CH₂CH₂(4-F)Ph CH₃ CH₃ H N C S CH₂CH₂(3-F)Ph CH₃ CH₃ H N C S CH₂CH₂(3-F)Ph CH₃ CH(CH₃)₂ H N C S CH₂CH₂(4-F)Ph CH₃ CH(CH₃)₂ H N C S CH₂CH₂Ph H CH₂CH₂ H CH₂CH₃ N C S CH₂CH₂Ph CH₃ CH₂CH₂ H CH₂CH₃ N C S CH₂CH₂Ph H cyclopentyl H N C S CH₂CH₂Ph CH₃ cyclopentyl H N C S CH₂Ph H cyclopentyl H N C S CH₂Ph CH₃ cyclopentyl H N C S CH₂CH₂(3-OCH₃)Ph H cyclopentyl H N C S CH₂CH₂(3-OCH₃)Ph CH₃ cyclopentyl H N C S CH₂CH₂(4-OCH₃)Ph H cyclopentyl H N C S CH₂CH₂(4-OCH₃)Ph CH₃ cyclopentyl H N C S CH₂CH₂(4-OCH₃)Ph H CH₂CH₃ H N C S CH₂CH₂(4-F)Ph H CH₂CH₃ H N C S CH₂CH₂(3-F)Ph H CH₂CH₃ H N C S CH₂CH₂(3-OCH₃)Ph H CH₂CH₃ H N C S CH₂CH₂(4-OCH₃)Ph CH₃ CH₂CH₃ H N C S CH₂CH₂(4-F)Ph CH₃ CH₂CH₃ H N C S CH₂CH₂(3-F)Ph CH₃ CH₂CH₃ H N C S CH₂CH₂(3-OCH₃)Ph CH₃ CH₂CH₃ H N C S CH₂CH₂(3-F)Ph H CF₃ H N C S CH₂CH₂(4-F)Ph H CF₃ H N C S CH₂CH₂(3-OCH₃)Ph H CF₃ H N C S CH₂CH₂(4-OCH₃)Ph H CF₃ H N C S CH₂CH₂(3-OCH₃)Ph CH₃ CF₃ H N C S CH₂CH₂(3-F)Ph CH₃ CF₃ H N C S CH₂CH₂(4-OCH₃)Ph CH₃ CF₃ H N C S CH₂CH₂(4-F)Ph CH₃ CF₃ H CH C═CH CH CH₂CH₂(4-F)Ph H 2-CH₃ 8F CH C═CH CH CH₂CH₂(4-F)Ph CH₃ 2-CH₃ 8F CH C═CH CH CH₂CH₂(4-F)Ph H 2-CH(CH₃)₂ 8F CH C═CH CH CH₂CH₂(4-F)Ph CH₃ 2-CH(CH₃)₂ 8F CH C═CH CH CH₂CH₂(3-F)Ph H 2-CH(CH₃)₂ H CH C═CH CH CH₂CH₂(3-F)Ph CH₃ 2-CH(CH₃)₂ H CH CH═C CH CH₂CH₂Ph H 3-CH₃ H CH CH═C CH CH₂CH₂Ph CH₃ 3-CH₃ H CH CH═C CH CH₂CH₂(3-F)Ph H 3-CH₃ H CH CH═C CH CH₂CH₂(3-F)Ph CH₃ 3-CH₃ H CH C═CH CH CH₂CH₂Ph H 2-CH₃ H CH C═CH CH CH₂CH₂Ph CH₃ 2-CH₃ H CH CH═C CH CH₂Ph H 3-H 8Cl CH CH═C CH CH₂CH₂Ph H 3-H 8Cl CH CH═C CH CH₂CH₂Ph CH₃ 3-H 8Cl CH CH═C CH CH₂Ph CH₃ 3-H 8Cl N N N CH₂CH₂Ph H CH(CH₃)₂ H N N N CH₂CH₂Ph CH₃ CH(CH₃)₂ H CH C S (S,R)CH₂CH(OH)Ph H CH₃ H CH C S (S,S)CH₂CH(OH)Ph H CH₃ H CH C S (S,S)CH₂CH(OH)Ph CH₃ CH₃ H N C S (S,R)CH₂CH(OH)Ph H CH(CH₃)₂ H N C S (S,S)CH₂CH(OH)Ph H CH(CH₃)₂ H N C S (S,S)CH₂CH(OH)Ph CH₃ CH(CH₃)₂ H CH C═CH CH CH₂CH₂(4-OCH₃)Ph H 2-CF₃ 8F CH C═CH CH CH₂CH₂(4-OCH₃)Ph CH₃ 2-CF₃ 8F CH C═CH CH CH₂CH₂(4-F)Ph H 2-CF₃ 8F CH C═CH CH CH₂CH₂(4-F)Ph CH₃ 2-CF₃ 8F

and all salts, solvates and crystal forms thereof.
 12. A compound of claim 1 found in Table 2: TABLE 2 (Ib)

Alk-Ar R¹ R² Z CH₂CH₂Ph H H 9F CH₂CH₂Ph CH₃ H 9F CH₂CH₂(4-OCH₃)Ph H H 9F CH₂CH₂(3-OCH₃)Ph H H 9F CH₂CH₂(3-F)Ph H H 9F CH₂CH₂(4-F)Ph H H 9F CH₂CH₂(4-OCH₃)Ph CH₃ H 9F CH₂CH₂(3-OCH₃)Ph CH₃ H 9F CH₂CH₂(3-F)Ph CH₃ H 9F CH₂CH₂(4-F)Ph CH₃ H 9F

and all salts, solvates and crystal forms thereof.
 13. The compounds of claim 1 that are: 2-Methyl-10-(4-methyl-3-(S)(2-methoxyphenyl)methyl-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene, 2-Methyl-10-(4-methyl-3-(S)(2-methoxyphenyl)ethyl-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene, 2-Methyl-10-(4-methyl-3-(S)phenethyl-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene, 10-[3-(2-Furan-3-yl-ethyl)-4-methyl-piperazin-1-yl]-2-methyl-4H-3-thia-4,9-diaza-benzo[f]azulene, 2-Methyl-10-(4-methyl-3-(S)phenylmethyl-piperazin-1-yl)-4H-3-thia-4,9-diaza-benzo[f]azulene, 2-Methyl-10-(4-methyl-(S)-3-phenethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene, 2-Methyl-10-(4-methyl-(S)-3-(2-methoxyphenyl)ethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene, 2-Methyl-10-(4-methyl-(S)-3-(4-methoxyphenyl)ethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene, 2-Methyl-10-(4-methyl-(S)-3-(4-methoxyphenyl)methyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene, 2-Ethyl-10-(4-methyl-(S)-3-(4-methoxyphenyl)ethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene, 2-Isopropyl-10-(4-methyl-(S)-3-phenethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene, 2-Isopropyl-10-(4-methyl-(S)-3-(3-fluorophenyl)ethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene, 2-Isopropyl-10-(4-methyl-(S)-3-(4-fluorophenyl)ethyl-piperazin-1-yl)-4H-3-thia-1,4,9-triaza-benzo[f]azulene, 2-Isopropyl-10-(4-methyl-3-phenethyl-piperazin-1-yl)-2,4-dihydro-1,2,3,4,9-pentaaza-benzo[f]azulene.
 14. A compound of structure:

wherein, R² is H, (C₁₋₆) alkyl, halogen, fluorinated (C₁₋₆) alkyl, OR⁴, SR⁴, NO₂, CN, COR⁴, CONR⁵R⁶, SO₂NR⁵R⁶, NR⁵R⁶, NR⁵COR⁴, NR⁵SO₂R⁴, or optionally substituted phenyl, wherein R⁴ is hydrogen, (C₁₋₆) alkyl, fluorinated (C₁₋₆) alkyl, benzyl, or optionally substituted phenyl, R⁵ and R⁶ are independently hydrogen, (C₁₋₆) alkyl, or optionally substituted phenyl; Z is one or two substituents independently selected from hydrogen, halogen, (C₁₋₆) alkyl, fluorinated (C₁₋₆) alkyl, OR⁷, SR⁷, NO₂, CN, COR⁷, CONR⁸R⁹, SO₂NR⁸R⁹, NR⁸SO₂R⁷, NR⁸R⁹, or optionally substituted phenyl, wherein R⁷ is hydrogen, (C₁₋₆) alkyl, fluorinated (C₁₋₆) alkyl, benzyl, or optionally substituted phenyl, R⁸ and R⁹ are independently hydrogen, (C₁₋₆) alkyl, or optionally substituted phenyl; and acid addition salts thereof.
 15. A compound of structure:

wherein, R² is H, (C₁₋₆) alkyl, halogen, fluorinated (C₁₋₆) alkyl, OR⁴, SR⁴, NO₂, CN, COR⁴, CONR⁵R⁶, SO₂NR⁵R⁶, NR⁵R⁶, NR⁵COR⁴, NR⁵SO₂R⁴, or optionally substituted phenyl, wherein R⁴ is hydrogen, (C₁₋₆) alkyl, fluorinated (C₁₋₆) alkyl, benzyl, or optionally substituted phenyl, R⁵ and R⁶ are independently hydrogen, (C₁₋₆) alkyl, or optionally substituted phenyl; Z is one or two substituents independently selected from hydrogen, halogen, (C₁₋₆) alkyl, fluorinated (C₁₋₆) alkyl, OR⁷, SR⁷, NO₂, CN, COR⁷, CONR⁸R⁹, SO₂NR⁸R⁹, NR⁸SO₂R⁷, NR⁸R⁹, or optionally substituted phenyl, wherein R⁷ is hydrogen, (C₁₋₆) alkyl, fluorinated (C₁₋₆) alkyl, benzyl,or optionally substituted phenyl, R⁸ and R⁹ are independently hydrogen, (C₁₋₆) alkyl, or optionally substituted phenyl; and acid addition salts thereof.
 16. A compound of structure:

wherein Ar is optionally substituted phenyl, naphthyl, monocyclic heteroaromatic, or bicyclic heteroaromatic, with the proviso that Ar may not be phenyl; and acid addition salts thereof.
 17. Compounds of claim 16 in which the stereo configuration is “S” about the carbon of the piperazine group bound to Alk.
 18. Compounds of claim 16 in which the stereo configuration is “R” about the carbon of the piperazine group bound to Alk.
 19. A compound of formula (1a)

wherein, Alk is (C₁₋₄) alkylene optionally substituted with OH; Ar is optionally substituted phenyl, naphthyl, monocyclic heteroaromatic, or bicyclic heteroaromatic; R¹ is hydrogen or (C₁₋₄) alkyl; R² is H, (C₁₋₆) alkyl, fluorinated (C₁₋₆) alkyl, Z is one or two substituents independently selected from hydrogen, or halogen, and salts, solvates, and crystal forms thereof.
 20. Compounds of claim 19 in which the stereo configuration is “S” about the carbon of the piperazine group bound to Alk.
 21. Compounds of claim 19 in which the stereo configuration is “R” about the carbon of the piperazine group bound to Alk.
 22. A compound of formula (1b)

wherein, Alk is (C₁₋₄) alkylene; Ar is optionally substituted phenyl, R¹ is hydrogen or (C₁₋₄) alkyl; R² is H, or (C₁₋₆) alkyl; Z is one or two substituents independently selected from hydrogen, or halogen; and salts, solvates, and crystal forms thereof.
 23. Compounds of claim 22 in which the stereo configuration is “S” about the carbon of the piperazine group bound to Alk.
 24. Compounds of claim 22 in which the stereo configuration is “R” about the carbon of the piperazine group bound to Alk.
 25. A Compound of Formula (1c)

wherein: Alk is (C₁₋₄) alkylene optionally substituted with OH; Ar is optionally substituted phenyl; R¹ is hydrogen or (C₁₋₄) alkyl; R² is H, (C₁₋₆) alkyl, halogen, or fluorinated (C₁₋₆) alkyl; Z is one or two substituents independently selected from hydrogen, or halogen; and salts, solvates, and crystal forms thereof.
 26. Compounds of claim 25 in which the stereo configuration is “S” about the carbon of the piperazine group bound to Alk.
 27. Compounds of claim 25 in which the stereo configuration is “R” about the carbon of the piperazine group bound to Alk.
 28. A Compound of Formula (1d)

wherein: Alk is (C₁₋₄) alkylene; Ar is optionally substituted phenyl; R¹ is hydrogen or (C₁₋₄) alkyl; R² is H, or (C₁₋₆) alkyl; Z is one or two substituents independently selected from hydrogen, or halogen; and salts, solvates, and crystal forms thereof.
 29. Compounds of claim 28 in which the stereo configuration is “S” about the carbon of the piperazine group bound to Alk.
 30. Compounds of claim 28 in which the stereo configuration is “R” about the carbon of the piperazine group bound to Alk.
 31. A compound of Formula (1e)

wherein, Alk is (C₁₋₄) alkylene; Ar is optionally substituted phenyl; R¹ is hydrogen or (C₁₋₄) alkyl; R² is H, (C₁₋₆) alkyl, halogen, fluorinated (C₁₋₆) alkyl, or CN; Z is one or two substituents independently selected from hydrogen, or halogen; and salts, solvates, and crystal forms thereof.
 32. Compounds of claim 31 in which the stereo configuration is “S” about the carbon of the piperazine group bound to Alk.
 33. Compounds of claim 31 in which the stereo configuration is “R” about the carbon of the piperazine group bound to Alk.
 34. A pharmaceutical composition comprising an effective amount of a compound of claim 1 in association with a pharmaceutically acceptable carrier, diluent or excipient.
 35. A pharmaceutical composition, comprising a compound of claim 1 in an amount effective to antagonize D₂ receptor stimulation, and a pharmaceutically acceptable carrier, diluent or excipient.
 36. A method for treatment of a condition which is treatable by reducing D₂ receptor stimulation, comprising administering to the mammal in need thereof a composition according to claim
 35. 37. A pharmaceutical composition, comprising a compound of claim 1 in an amount effective to antagonize 5-HT_(2A) receptor stimulation, and a pharmaceutically acceptable carrier, diluent or excipient.
 38. A method for treatment of a condition which is treatable by reducing 5-HT_(2A) receptor stimulation, comprising administering to the mammal in need thereof a composition according to claim
 37. 39. A pharmaceutical composition, comprising a compound of claim 1 in an amount effective to antagonize 5-HT₆ receptor stimulation, and a pharmaceutically acceptable carrier, diluent or excipient.
 40. A method for treatment of a condition which is treatable by reducing 5-HT₆ receptor stimulation, comprising administering to the mammal in need thereof a composition according to claim
 39. 41. A method for antagonizing dopamine receptor D₂, comprising administering to a mammal an effective amount of a compound of claim
 1. 42. A method for antagonizing the 5-HT_(2A) receptor, comprising administering to a mammal an effective amount of a compound of claim
 1. 43. A method for antagonizing the 5-HT₆ receptor, comprising administering to a mammal an effective amount of a compound of claim
 1. 44. A method for treating a psychotic disorder, comprising administering to a mammal in need of such treatment, an effective amount of a compound of claim
 1. 45. The method of claim 44, wherein the psychotic disorder is schizophrenia.
 46. The method of claim 44, wherein the psychotic disorder is schizophreniform.
 47. The method of claim 44, wherein the psychotic disorder is schizoaffective.
 48. A method for treating a mood disorder, comprising administering to a mammal in need of such treatment, an effective amount of a compound of claim
 1. 49. The method of claim 48, wherein the mood disorder is bipolar disorders.
 50. A method for preparing a compound of the formula

comprising: reacting a compound of formula

with a piperazine of formula

wherein: Alk is (C₁₋₄) alkylene optionally substituted with OH, methoxy, ethoxy, or F; Ar is optionally substituted phenyl, naphthyl, monocyclic heteroaromatic, or bicyclic heteroaromatic; R¹ is hydrogen or (C₁₋₄) alkyl optionally substituted with OH, OR³, or OCH₂CH₂OH, wherein R³ is (C₁₋₂) alkyl; R² is H, (C₁₋₆) alkyl, halogen, fluorinated (C₁₋₆) alkyl, OR⁴, SR⁴, NO₂, CN, COR⁴, CONR⁵R⁶, SO₂NR⁵R⁶, NR⁵R⁶, NR⁵COR⁴, NR⁵SO₂R⁴, or optionally substituted phenyl, wherein R⁴ is hydrogen, (C₁₋₆) alkyl, fluorinated (C₁₋₆) alkyl, benzyl, or optionally substituted phenyl, R⁵ and R⁶ are independently hydrogen, (C₁₋₆) alkyl, or optionally substituted phenyl; Z is one or two substituents independently selected from hydrogen, halogen, (C₁₋₆) alkyl, fluorinated (C₁₋₆) alkyl, OR⁷, SR⁷, NO₂, CN, COR⁷, CONR⁸R⁹, SO₂NR⁸R⁹, NR⁸SO₂R⁷, NR₈R⁹, or optionally substituted phenyl, wherein R⁷ is hydrogen, (C₁₋₆) alkyl, fluorinated (C₁₋₆) alkyl, benzyl, or optionally substituted phenyl, R⁸ and R⁹ are independently hydrogen, (C₁₋₆) alkyl, or optionally substituted phenyl.
 51. The method of claim 50 wherein the compound of formula

is prepared by cyclizing a compound of formula


52. The method of claim 51 wherein the compound of formula

is prepared by reacting a compound of formula

with a compound of formula

and wherein Y₁₁ is fluorine or chlorine.
 53. The method of claim 52 wherein the compound of formula

is prepared by reducing a compound of formula


54. The method of claim 53 wherein the compound of formula

is prepared from a compound of formula


55. The method of claim 54 wherein the compound of formula

is prepared by nitrating a compound of formula


56. The method of claim 55 wherein the compound of formula

is prepared by brominating a compound of formula 